U.S. patent number 7,655,038 [Application Number 10/790,338] was granted by the patent office on 2010-02-02 for polymeric network system for medical devices and methods of use.
This patent grant is currently assigned to BioInteractions Ltd.. Invention is credited to Ajay K. Luthra, Shivpal S. Sandhu.
United States Patent |
7,655,038 |
Luthra , et al. |
February 2, 2010 |
Polymeric network system for medical devices and methods of use
Abstract
Methods of making a coating on a medical device are disclosed,
including associating a composition with at least a portion of the
device to form a layer. In some embodiments, a composition may
include a copolymer prepared from a room temperature melt of a
plurality of monomer units that comprises a first monomer unit and
a second monomer unit, wherein the second monomer unit has a glass
transition temperature that is at least about 30 degrees Centigrade
higher than the glass transition temperature of the first monomer
unit, with a glass transition temperature of a monomer unit being
defined as a glass transition temperature of a homopolymer of that
monomer unit.
Inventors: |
Luthra; Ajay K. (Ruislip,
GB), Sandhu; Shivpal S. (Slough, GB) |
Assignee: |
BioInteractions Ltd. (Reading,
Berkshire, GB)
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Family
ID: |
32927706 |
Appl.
No.: |
10/790,338 |
Filed: |
March 1, 2004 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20040170752 A1 |
Sep 2, 2004 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60451333 |
Feb 28, 2003 |
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Current U.S.
Class: |
623/1.42;
623/1.46; 526/319; 526/318; 526/317.1; 428/520; 428/213 |
Current CPC
Class: |
A61L
31/04 (20130101); A61L 31/16 (20130101); C09D
133/04 (20130101); C08F 220/18 (20130101); C09D
133/06 (20130101); A61L 31/10 (20130101); C08F
220/1804 (20200201); B32B 27/30 (20130101); A61L
31/10 (20130101); C08L 33/08 (20130101); A61L
2300/606 (20130101); C08F 220/1812 (20200201); A61L
2300/608 (20130101); A61L 2420/02 (20130101); Y10T
428/2495 (20150115); Y10T 428/31928 (20150401); A61L
2300/416 (20130101) |
Current International
Class: |
A61F
2/06 (20060101); B32B 27/08 (20060101); B32B
7/02 (20060101); C08F 120/06 (20060101) |
Field of
Search: |
;428/213,520
;526/317.1,318,319 ;623/1.42,1.46 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0425200 |
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May 1991 |
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EP |
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09/50386 |
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Oct 1999 |
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EP |
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WO 00/41687 |
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Jul 2000 |
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WO |
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WO 00/41738 |
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Jul 2000 |
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WO |
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WO 01/01890 |
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Jan 2001 |
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WO |
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WO 01/87342 |
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Nov 2001 |
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WO |
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WO 03/024500 |
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Mar 2003 |
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WO |
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WO 2004/009145 |
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Jan 2004 |
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WO |
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Primary Examiner: Kruer; Kevin R.
Attorney, Agent or Firm: Dardi & Herbert, PLLC
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims the benefit to U.S. Provisional
Patent Application Ser. No. 60/451,333, filed Feb. 28, 2003, which
is hereby incorporated by reference.
Other copending applications that are commonly owned and assigned,
and may be related with respect to some subject matter, are U.S.
patent applications Ser. Nos. 10/179,453, filed Jun. 26, 2002, and
10/750,706, filed Jan. 5, 2004, which are hereby incorporated by
reference without a claim of priority.
Claims
The invention claimed is:
1. A coating for a medical device for delivery of a therapeutic
agent, the coating comprising a layer with a thickness between
about 0.1 .mu.m and about 1000 .mu.m and having a composition
associated with at least a portion of the device, wherein the
composition comprises the therapeutic agent associated with
copolymer free of covalent crosslinks that has a weight averaged
molecular weight of at least about 2500, wherein the copolymer
comprises a first monomer unit and a second monomer unit, wherein
the second monomer unit has a glass transition temperature that is
at least about 30 degrees Centigrade higher than the glass
transition temperature of the first monomer unit, with a glass
transition temperature of a monomer unit being defined as a glass
transition temperature of a homopolymer of that monomer unit.
2. The coating of claim 1 wherein at least a portion of the first
monomer units are organized into a plurality of blocks consisting
essentially of repeats of the first monomer unit, and at least a
portion of the second monomer units are organized into a plurality
of blocks consisting essentially of repeats of the second monomer
unit.
3. The coating of claim 2 wherein the copolymer further comprises
regions of random copolymer bonding.
4. The coaling of claim 1 wherein the copolymer comprises a third
monomer unit and comprises at least three blocks, wherein each
block consists essentially of repeats of one type of monomer
unit.
5. The coating of claim 1 wherein the copolymer comprises acrylate
blocks and methacrylate blocks.
6. The coating of claim 1 wherein the therapeutic agent associates
with blocks within the copolymer.
7. The coating of claim 1 wherein the second monomer unit has a
glass transition temperature that is at least about 50 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit.
8. The coating of claim 1, wherein the second monomer unit has a
glass transition temperature that is at least about 70 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit.
9. The coating of claim 1 wherein the first monomer unit comprises
an acrylate and the second monomer unit compromises a
methacrylate.
10. The coating of claim 1 wherein the first monomer unit and the
second monomer unit selected from a member of the group consisting
of acrylic acid, acrlonitrile, allyamine, acrylates, methacrylates,
methylmethacrylate, alkyl acrylates, alkyl methacrylate, butadiene,
carbomethylsilane, (carbonate) urethane, acrylates of polydimethyl
siloxanes, methacrylates of polydimethyl siloxanes, ethylene,
ethylene glycol, propylene glycol, (ether) urethane, urethane,
vinyl chloride, vinyl alcohol, maleic anhydride, cellulose nitrate,
carboxy methyl cellulose, dextran, dextran sulphate, propylene,
esters, carbonates, ethers, butenes, maleic acid, fluoropolymer
monomeric units, unsaturated polymer monomeric units, isoprene,
melamine, sulphone, ureas, biological polymer monomeric units,
protein, gelatin, collagen, elastin, butyl methacrylate,
hydroxyethyl methacrylate, methacrylate acid, polyethylene glycol
dimethacrylate, polypropylene glycol diglycidal ether, polyethylene
glycol diglycidyl ether, isocyanatoethyl methacrylate,
N-acryloxysuccinimide, glycidyl methacrylate, hexamethylene
diisocyanate, acrolein, crotonaldehyde, glycerol monomethacrylate,
heparin methacrylate, methacryloylethyl phosphorylcholine,
polymethacrylatea, polyacrylate, polyester, polyether, polyethylene
glycol, butyl acrylate, polyethylene glycol monomethacrylate,
isobutyl methacrylate, cyclohexyl methacrylate, ethyl acrylate,
2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, ethyl
methacrylate, methyl acrylate, hexadecyl methacrylate, octadecyl
methacrylate, styrene, methyl styrene, vinyl sterate, vinyl
toluene, and tert-butyl acrylate.
11. The coating of claim 1 wherein the copolymer father comprises a
third monomer unit, wherein the third monomer unit forms a
homopolymer wit a glass transition temperature that is at least
about 30 degrees Centigrade higher than the glass transition
temperature of a homopolymer formed by the first monomer unit.
12. The coating of claim 11 wherein the first monomer unit
comprises an acrylate, the second monomer unit compromises a
methacrylate, and the third monomer unit comprises a
methacrylate.
13. The coating of claim 11 wherein the copolymer comprises a
homopolymer of the first monomer unit covalently joined to a
homopolymer of the second monomer unit.
14. The coating of claim 13 wherein a first polymer comprises a
first monomer unit and a second polymer comprises at least one
member of the group consisting of the first monomer unit, the
second monomer unit, and both the first monomer unit and the second
monomer unit.
15. The coating of claim 1 wherein the copolymer comprises at least
two methacrylate monomer units.
16. The coating of claim 1 wherein the copolymer comprises a member
of the group consisting of poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate),
poly(hydroxyethyl methacrylate-co-lauryl methacrylate),
poly(polyethylene glycol monomethacrylate-co-butyl
acrylate-co-butyl methacrylate), poly(heparin
methacrylate-co-hydroxyethylmethacrylate-co-butyl acrylate-co-butyl
methacrylate), poly(glycerol monomethacrylate-co-butyl
acrylate-co-butyl methacrylate), poly(amino methacrylate
hydrochloride-co-butyl acrylate-co-butyl methacrylate),
poly(isocyanatoethyl methacrylate-co-butyl acrylate-co-butyl
methacrylate) and poly (methoxy(polyethylene glycol)
monomethacrylate-co-lauryl methacrylate-co-butyl
methacrylate-co-ethylene glycol dimethacrylate).
17. The coating of claim 1 wherein the monomer units are
polymerizable to form the copolymer after the monomer units have
been associated with the medical device.
18. The coating of claim 1 wherein the medical device is a stent
and the therapeutic agent is paclitaxel.
19. The coating of claim 1 wherein the copolymer is prepared and is
subsequently associated with the therapeutic agent.
20. The coating of claim 1 wherein the copolymer is prepared from
the monomer units from a melt of the monomers.
21. The coating of claim 1 wherein the first monomer unit and the
second monomer unit are chosen so that the first monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the first monomer unit and the second monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the second monomer unit.
22. The coating of claim 1 further comprising a second layer that
contacts at least a portion of the first layer, wherein the second
layer and the first layer have a different composition.
23. The coating of claim 22 wherein the first layer is at least
partially disposed between the device and the second layer.
24. The coaling of claim 22 wherein the second layer is at least
partially disposed between the device and the first layer.
25. The coating of claim 22 wherein the second layer comprises a
polymer that is covalently crosslinked to a polymer of the first
layer.
26. The coating of claim 25 wherein the copolymer comprises
reactive functional groups that are involved in forming covalent
crosslinks with the second layer, and wherein the reactive
functional groups are chosen from the group consisting of hydroxyl,
amine, carboxylic, aldehyde, ketone, thiol, ally), acrylate,
methacrylate, isocyanate, epoxide, azides, aziridines, acetals,
ketals, alkynes, acyl halides, alky halides, hydroxy aldehydes and
ketones, allenes, amides, bisamides, amino acids and esters, amino
carbonyl compounds, mercaptans, amino mercaptans, anhydrides,
azines, azo compounds, azoxy compounds, boranes, carbamates,
carbodimides, carbonates, diazo compounds, isothionates, hydroxamic
acid, hydroxy acids, hydroxy amines and amides, hydroxylamine,
imines, lactams, nitriles, sulphonamides, sulphones, sulphonic
acids, thiocyanates, and combinations thereof.
27. The coating of claim 25 wherein the second layer comprises a
heparin macromer that comprises a second reactive functional group
that is involved in forming the crosslinks with the first
layer.
28. The coating of claim 25 wherein the polymer of the second layer
comprises monomer units that comprise a heparin macromer.
29. The coating of claim 25 wherein the polymer of the second layer
comprises a second functional group that forms at least one of the
covalent crosslinks in response to exposure to light.
30. The coating of claim 29 wherein the second functional group
comprises azide.
31. The coating of claim 22 wherein the first layer comprises the
therapeutic agent and the second layer does not comprise the
therapeutic agent.
32. The coating of claim 22 wherein the second layer reduces the
rate of release of the therapeutic agent from the first layer.
33. The coating of claim 22 wherein the second layer is in contact
with the medical device and comprises a polymer having at least one
reactable monomer.
34. The coating of claim 33 wherein the at least one reactable
monomer is a member of the group consisting of acrylates and
methylmethacrylates.
35. The coating of claim 34 wherein the polymer in the second layer
is a second copolymer that comprises monomer units of at least one
member of the group consisting of vinyl chloride, vinyl acetate,
and co-vinyl alcohol.
36. The coating of claim 34 wherein the polymer in the second layer
comprises a hydrophillic polymer.
37. The coating of claim 36 wherein the polymer in the second layer
comprises polyvinylpyrrolidone.
38. The coating of claim 22 further comprising a third layer having
a composition different from the first layer and the second
layer.
39. The coating of claim 1 wherein the therapeutic agent is a
member of the group consisting of, vasoactive agents, neuroactive
agents, hormones, growth factors, cytokines, anaesthetics,
steroids, anticoagulants, anti-inflammatories, immunomodulating
agents, cytotoxic agents, antibiotics, antivirals, antibodies,
anti-thrombogenic agents such as heparin, heparin derivatives,
urokinase, and PPack (dextrophenylalanine proline arginine
chloromethylketone); anti-proliferative agents such as enoxaprin,
angiopeptin, antibodies capable of blocking smooth muscle cell
proliferation, hirudin, acetylsalicylic acid; anti-inflammatory
agents, dexamethasone, prednisolone, corticosterone, budesonide,
estrogen, sulfasalazine, and mesalamine, 5-fluorouracil, cisplatin,
vinblastine, vincristine, epothilones, endostatin, angiostatin and
thymidine kinase inhibitors; anesthetic agents such as lidocaine,
bupivacaine, and ropivacaine; anti-coagulants, D-Phe-Pro-Arg
chloromethyl ketone, an RGD peptide-containing compound, heparin,
antithrombin compounds, platelet receptor antagonists,
anti-thrombin, anti-platelet receptor antibodies, aspirin,
prostaglandin inhibitors, platelet inhibitors, antiplatelet
peptides, vascular cell growth promoters, growth factor inhibitors,
growth factor receptor antagonists, transcriptional activators,
translational promoters, vascular cell growth inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
cholesterol-lowering agents, vasodilating agents, agents which
interfere with endogenous vasoactive mechanisms, a
radiopharmaceutical, an analgesic drug, an anesthetic agent, an
anorectic agent, an anti-anemia agent, an anti-asthma agent, an
anti-diabetic agent, an antihistamine, an anti-inflammatory drug,
an antibiotic drug, an antimuscarinic drug, an anti-neoplastic
drug, an antiviral drug, a cardiovascular drug, a central nervous
system stimulator, a central nervous system depressant, an
anti-depressant, an anti-epileptic, an anxyolitic agent, a hypnotic
agent, a sedative, an anti-psychotic drug, a beta blocker, a
hemostatic agent, a hormone, a vasodilator, a vasoconstrictor, and
a vitamin.
40. The coating of claim 1 wherein the therapeutic agent comprises
paclitaxel.
41. The coating of claim 1 wherein the device is selected from the
group consisting of an implantable device, a device used topically
on a patient, a device that contacts a living tissue, a catheter; a
guide-wires, an embolizing coil; a vascular graft, a heart valve,
an implantable cardiovascular defibrillator, a pacemaker, a
surgical patch, a wound closure, a microsphere, a biosensors, an
implantable sensor, an ex-vivo sensor, an ocular implant, a contact
lens; and a tissue engineering scaffold.
42. The coating of claim 1 wherein the device comprises a
stent.
43. The coating of claim 1 wherein the glass transition temperature
of the first monomer unit is below about 37 degrees Centigrade and
the glass transition temperature of the second monomer unit is
above about 37 degrees Centigrade.
44. The coating of claim 1 wherein the copolymer is made from a
combination of monomer units and has a glass transition temperature
in a range of about 0 to about 60 degrees Celsius as measured using
differential scanning calorimetery.
45. The coating of claim 1 wherein the copolymer is made from a
combination of monomer units and has a glass transition temperature
in a range of about 15 to about 40 degrees Celsius as measured
using differential scanning calorimetery.
46. The coating of claim 1 wherein the copolymer is made from a
combination of monomer units and has a glass transition temperature
in a range of about -70 to about 70 degrees Celsius as measured
using differential scanning calorimetery.
47. The coating of claim 46 wherein the combination comprises at
least one monomer unit selected from the group consisting of butyl
acrylate, butyl methylmethacrylate, and
hydroxyethylmethacrylate.
48. The coating of claim 46 wherein the first monomer unit and the
second monomer unit are selected from a member of the group
consisting of acrylic acid, acrionitrile, allyamine, acrylates,
methacrylates, methylmethacrylate, alkyl acrylates, alkyl
methacrylate, butadiene, carbomethylsilane, (carbonate) urethane,
acrylates of polydimethyl siloxanes / methacrylates of polydimethyl
siloxane ethylene, ethylene glycol, propylene glycol, (ether)
urethane, urethane, vinyl chloride, vinyl alcohol, maleic
anhydride, cellulose nitrate, carboxy methyl cellulose, dextran,
dextran sulphate, propylene, esters, carbonates, ethers, butenes,
maleic acid, fluoropolymer monomeric units, unsaturated polymer
monomeric units, isoprene, melamine, sulphone, ureas, biological
polymer monomeric units, protein, gelatin, collagen, elastin, butyl
methacrylate, hydroxyethyl methacrylate, acrylic acid, methacrylate
acid, polyethylene glycol dimethacrylate, polypropylene glycol
diglycidal ether, polyethylene glycol diglycidyl ether,
isocyanatoethyl methacrylate, N-acryloxysuccinimide, glycidyl
methacrylate, hexamethylene diisocyanate, acrolein, crotonaldehyde,
glycerol monomethacrylate, heparin methacrylate,
methacryloyloxyethyl, methacryloylethyl phosphorylcholine
polyacrylate, polyester, polyether, polyethylene glycol, butyl
acrylate, polyethylene glycol monomethacrylate, isobutyl
methacrylate, cyclohexyl methacrylate, ethyl acrylate,
2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, ethyl
methacrylate, methyl acrylate, hexadecyl methacrylate, octadecyl
methacrylate, styrene, methyl styrene, vinyl sterate, vinyl
toluene, and tert-butyl acrylate.
49. The coating of claim 46 wherein the copolymer further comprises
a third monomer unit, wherein the third monomer unit forms a
homopolymer with a glass transition temperature that is at least
about 30 degrees Centigrade higher than the glass transition
temperature of a homopolymer formed by the first monomer unit.
50. The coating of claim 46 wherein the first monomer unit
comprises an acrylate, the second monomer unit compromises a
methacrylate, and the third monomer unit comprises a
methacrylate.
51. The coating of claim 46 wherein the copolymer comprises at
least two methacrylate monomer units.
52. The coating of claim 42 wherein the coating is disposed
essentially only on the solid portions of the stent.
53. The coating of claim 42 wherein the coating is disposed on both
a lumen and exterior of the stent.
54. An expandable medical device associated with a material
composition for delivery of a therapeutic agent, comprising: an
expandable portion of an expandable stern coated with a composition
comprising the therapeutic agent associated with a copolymer free
of covalent crosslinks that has a weight averaged molecular weight
of at least about 2500, wherein the copolymer comprises a first
monomer unit and a second monomer unit, wherein the second monomer
unit has a glass transition temperature that is at least about 30
degrees Centigrade higher than the glass transition temperature of
the first monomer unit, with a glass transition temperature of a
monomer unit being defined as a glass transition temperature of a
homopolymer of that monomer unit.
55. The device of claim 54 wherein at least a portion of the first
monomer units are organized into a plurality of blocks consisting
essentially of repeats of the first monomer unit, and at least a
portion of the second monomer units are organized into a plurality
of blocks consisting essentially of repeats of the second monomer
unit.
56. The device of claim 55 wherein the copolymer further comprises
regions of random copolymer bonding.
57. The device of claim 55 wherein the copolymer comprises acrylate
blocks and methacrylate blocks.
58. The device of claim 54 wherein the copolymer comprises a third
monomer unit and comprises at least three blocks, wherein each
block consists essentially of repeats of one type of monomer
unit.
59. The device of claim 54 wherein the therapeutic agent associates
with blocks within the copolymer.
60. The device of claim 54, wherein the second monomer unit has a
glass transition temperature that is at least about 70 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit.
61. The device of claim 54 wherein the monomer units are
polymerizable to form the copolymer after the monomer units have
been associated with the medical device.
62. The device of claim 54 wherein the therapeutic agent is
paclitaxel.
63. The device of claim 54 wherein the copolymer is prepared and is
subsequently associated with the therapeutic agent.
64. The device of claim 54 wherein the copolymer is prepared from
the monomer units from a melt of the monomers.
65. The device of claim 54 wherein the first monomer unit and the
second monomer unit are chosen so that the first monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the first monomer unit and the second monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the second monomer unit.
66. The device of claim 54 further comprising a second layer that
contacts at least a portion of the first layer, wherein the second
layer and the first layer have a different composition.
67. The device of claim 66 wherein the second layer comprises a
polymer that is covalently crosslinked to a polymer of the first
layer.
68. The device of claim 67 wherein the polymer of the second layer
comprises monomer units that comprise a heparin macromer.
69. The device of claim 66 wherein the polymer of the second layer
comprises a second functional group that forms at least one of the
covalent crosslinks in response to exposure to light.
70. The device of claim 54 wherein the copolymer glass transition
temperature is between 26 and about 40 degrees Centigrade.
71. The device of claim 54 wherein the composition associated with
the stent has a thickness ranging from about 0.1 .mu.m to about 30
.mu.m.
72. The coating of claim 1 wherein the thickness ranges from about
1 .mu.m to about 200 .mu.m.
73. The coating of claim 54 wherein the coating is disposed
essentially only on the solid portions of the stent.
74. The coating of claim 54 wherein the coating is disposed on both
a lumen and exterior of the stent.
75. A coating for a medical device for delivery of a therapeutic
agent, the coating comprising a layer having a composition
associated with at least a portion of the device, wherein the
composition comprises the therapeutic agent associated with a
copolymer that has a weight averaged molecular weight of at least
about 2500 and a glass transition temperature between 26 and about
40 degrees Centigrade as measured by differential scanning
calorimetery, wherein the copolymer comprises a first monomer unit
and a second monomer unit, wherein the second monomer unit has a
glass transition temperature that is at least about 30 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit, with a glass transition temperature of a
monomer unit being defined as a glass transition temperature of a
homopolymer of tat monomer unit, wherein the layer has a glass
transition temperature between 26 and about 40 degrees Centigrade
as measured by differential scanning calorimetery.
76. The coating of claim 75 wherein at least a portion of the first
monomer units are organized into a plurality of blocks consisting
essentially of repeats of the first monomer unit, and at least a
portion of the second monomer units are organized into a plurality
of blocks consisting essentially of repeats of the second monomer
unit.
77. The coating of claim 75 wherein the copolymer further comprises
regions of random copolymer bonding.
78. The coating of claim 75 wherein the copolymer comprises a third
monomer unit and comprises at least three blocks, wherein each
block consists essentially of repeats of one type of monomer
unit.
79. The coating of claim 75 wherein the copolymer comprises
acrylate blocks and methacrylate blocks.
80. The coating of claim 75 wherein the therapeutic agent
associates with blocks within the copolymer.
81. The coating of claim 75, wherein the second monomer unit has a
glass transition temperature that is at least about 70 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit.
82. The coating of claim 75 wherein the monomer units are
polymerizable to form the copolymer after the monomer units have
been associated with the medical device.
83. The coating of claim 75 wherein the medical device is a stent
and the therapeutic agent is paclitaxel.
84. The coating of claim 75 wherein the copolymer is prepared and
is subsequently associated with the therapeutic agent.
85. The coating of claim 75 wherein the copolymer is prepared from
the monomer units from a melt of the monomers.
86. The coating of claim 75 wherein the first monomer unit and the
second monomer unit are chosen so that the first monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the first monomer unit and the second monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the second monomer unit.
87. The coating of claim 75 further comprising a second layer that
contacts at least a portion of the first layer, wherein the second
layer and the first layer have a different composition.
88. The coating of claim 87 wherein the second layer comprises a
polymer that is covalently crosslinked to a polymer of the first
layer.
89. The coating of claim 88 wherein the polymer of the second layer
comprises monomer wilts that comprise a heparin macromer.
90. The coating of claim 88 wherein the polymer of the second layer
comprises a second functional group that forms at least one of the
covalent cross links in response to exposure to light.
91. The coating of claim 75 wherein the medical device is a stent,
with the coating being applied to every expandable portion of the
stent.
92. The coating of claim 75 wherein the medical device is a member
of the group consisting of an implantable device, a device used
topically on a patient, a device that contacts a living tissue, a
catheter; a guide-wires, an embolizing coil, an implantable lead,
an expandable balloon, a vascular graft, a heart valve, an
implantable cardiovascular defibrillator, a pacemaker, a surgical
patch, a wound closure, a microsphere, a biosensors, an implantable
sensor, an ex-vivo sensor, an ocular implant, a contact lens, and a
tissue engineering scaffold.
93. The coating of claim 75 having a thickness of between about 0.1
.mu.m and about 1000 .mu.m.
94. The coating of claim 75 having a thickness of between about 1
.mu.m and about 200 .mu.m.
95. The copolymer of claim 70 wherein the copolymer glass
transition temperature is about 37.degree.C.
96. The coating of claim 75 wherein the layer glass transition
temperature is about 37.degree.C.
97. A coaling for a medical device for delivery of a therapeutic
agent, the coating comprising a layer having a composition
associated wit at least a portion of the device, wherein the
composition comprises the therapeutic agent associated with a
copolymer free of covalent crosslinks that has a weight averaged
molecular weight of at least about 2500, wherein the copolymer
comprises a first monomer unit and a second monomer unit, wherein
the second monomer unit has a glass transition temperature that is
at least about 30 degrees Centigrade higher than the glass
transition temperature of the first monomer unit, with a glass
transition temperature of a monomer unit being defined as a glass
transition temperature of a homopolymer of that monomer unit,
wherein the device is selected from the group consisting of an
implantable device, a device used topically on a patient, a device
that contacts a living tissue, a catheter; a guide-wires, an
embolizing coil, an implantable lead, an expandable balloon, a
vascular graft, a heart valve, an implantable cardiovascular
defibrillator, a pacemaker, a surgical patch, a wound closure, a
microsphere, a biosensors, an implantable sensor, an ex-vivo
sensor, an ocular implant, a contact lens, and a tissue engineering
scaffold.
98. The coating of claim 97 wherein at least a portion of the first
monomer units are organized into a plurality of blocks consisting
essentially of repeats of the first monomer unit, and at least a
portion of the second monomer units are organized into a plurality
of blocks consisting essentially of repeats of the second monomer
unit.
99. The coating of claim 98 wherein the copolymer further comprises
regions of random copolymer bonding.
100. The coating of claim 97 wherein the copolymer comprises a
third monomer unit and comprises at least three blocks, wherein
each block consists essentially of repeats of one type of monomer
unit.
101. The coating of claim 97 wherein the copolymer comprises
acrylate blocks and methacrylate blocks.
102. The coating of claim 97 wherein the therapeutic agent
associates with blocks within the copolymer.
103. The coating of claim 97, wherein the second monomer unit has a
glass transition temperature that is at least about 70 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit.
104. The coating of claim 97 wherein the monomer units are
polymerizable to form the copolymer after the monomer units have
been associated with the medical device.
105. The coating of claim 97 wherein the copolymer is prepared and
is subsequently associated with the therapeutic agent.
106. The coating of claim 97 wherein the copolymer is prepared from
the monomer units from a melt of the monomers.
107. The coating of claim 97 wherein the first monomer unit and the
second monomer unit are chosen so that the first monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the first monomer unit and the second monomer unit
reacts to form a plurality of blocks consisting essentially of
repeats of the second monomer unit.
108. The coating of claim 97 further comprising a second layer that
contacts at least a portion of the first layer, wherein the second
layer and the first layer have a different composition.
109. The coating of claim 108 wherein the second layer comprises a
polymer that is covalently crosslinked to a polymer of the first
layer.
110. The coating of claim 109 wherein the polymer of the second
layer comprises monomer units that comprise a heparin macromer.
111. The coating of claim 109 wherein the polymer of the second
layer comprises a second functional group that forms at least one
of the covalent crosslinks in response to exposure to light.
112. The coating of claim 97 wherein the copolymer has a glass
transition temperature between 26 and about 40 degrees
Centigrade.
113. The coating of claim 97 having a thickness of between about
0.1 .mu.m and about 1000 .mu.m.
Description
FIELD OF THE INVENTION
The inventions are, in general, related to the field of coatings
for medical devices, and certain embodiments relate to drug
delivery using the same.
BACKGROUND
Coated medical devices, such as stents, catheters, guide wires,
vascular grafts and the like, are frequently used in numerous
medical procedures. The utility of these devices may be enhanced by
therapeutic, diagnostic, lubricious or other materials coated onto
the device which can be delivered, or released, from the device to
a specific site within the patient. With the number of medical
procedures utilizing medical devices such as stents and catheters,
it would be desirable to provide coated medical devices that
release therapeutic or diagnostic agents within a patient in a
controlled manner.
A conventional technique for introducing a drug into a medical
device coating is to apply the coating to the device, swell the
coating in a solvent in the presence of a drug that is dissolved in
the solvent, and to remove the solvent. The swelling of the coating
allows the drug to interpenetrate the coating, where it remains
after the solvent is removed.
SUMMARY OF THE INVENTION
Set forth herein are techniques that include loading a drug into a
copolymer before the copolymer-drug combination is coated onto a
device. This process is advantageous because the copolymer drug may
be deposited in a layer or series of layers to form a coating on
the medical device. Coatings intimately contact the device for
improved adherence and other properties helpful when the device is
implanted. Further, coatings are more conveniently adapted to
production processes than alternative processes such as molding a
sheath or packing a sheath around the device.
An embodiment is a method of making a coating on a medical device
for delivery of a therapeutic agent. For example, this method may
be done by associating a composition with at least a portion of the
device to form a first layer, wherein the composition comprises the
therapeutic agent associated with a copolymer that optionally has a
molecular weight of at least about 2500, wherein the copolymer
comprises a first monomer unit and a second monomer unit, wherein
the second monomer unit has a glass transition temperature that is
at least about 30 degrees Centigrade higher than the glass
transition temperature of the first monomer unit, with a glass
transition temperature of a monomer unit being defined as a glass
transition temperature of a homopolymer of that monomer unit. Such
methods may be optionally performed with the monomer units being
polymerized to form the copolymer after the monomer units have been
associated with the medical device.
Another embodiment is a coating for a medical device for delivery
of a therapeutic agent. The coating may include a layer having a
composition associated with at least a portion of the device,
wherein the composition comprises the therapeutic agent associated
with a copolymer that optionally has a molecular weight of at least
about 2500, wherein the copolymer comprises a first monomer unit
and a second monomer unit, wherein the second monomer unit has a
glass transition temperature that is at least about 30 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit, with a glass transition temperature of a
monomer unit being defined as a glass transition temperature of a
homopolymer of that monomer unit. Coatings formed by such methods
may optionally include a second layer that contacts at least a
portion of the first layer, wherein the second layer and the first
layer have a different composition.
Another embodiment is a method of making a coating on a medical
device by associating a composition with at least a portion of the
device to form a layer, wherein the composition comprises a
copolymer that optionally has a molecular weight of at least about
2500, wherein the copolymer is prepared from a room temperature
melt of a plurality of monomer units that comprises a first monomer
unit and a second monomer unit, wherein the second monomer unit has
a glass transition temperature that is at least about 30 degrees
Centigrade higher than the glass transition temperature of the
first monomer unit, with a glass transition temperature of a
monomer unit being defined as a glass transition temperature of a
homopolymer of that monomer unit. Such methods may be optionally be
performed with the monomer units being polymerized to form the
copolymer after the monomer units have been associated with the
medical device.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts in Frame (A) an illustration of domains formed by
blocks in copolymers, and possible mechanisms in Frames (B), (C)
and (D) of therapeutic drug association or entrapment
FIG. 2 shows examples of monomeric units, and also indicates the Tg
of homopolymers formed from such units.
FIG. 3 is a cross sectional view of an embodiment of a coating that
would be on a medical device.
FIG. 4 is a cross sectional view of an alternative embodiment of a
coating on a medical device.
FIG. 5 shows release of a therapeutic agent from a layer, as
further described in Example 8.
FIG. 6 shows release of a therapeutic agent from a layer, as
further described in Example 11.
FIG. 7 shows release of a therapeutic agent from a layer, as
further described in Example 13.
FIG. 8 shows release of a therapeutic agent from a layer, as
further described in Example 18.
FIG. 9 shows release of a therapeutic agent from a layer, as
further described in Examples 20 and 21.
DETAILED DESCRIPTION
Copolymers are described that form associations with therapeutic
agents so that the copolymer-agent complex may be used in
subsequent processing steps, e.g., forming a layer on a medical
device. Without being limited to a particular theory, the
advantageous properties presented by the copolymer domains may be
the result of primary, secondary and/or tertiary structure of the
resulting macromolecules. The domains may be created by the
association of blocks on the copolymers, as shown in FIG. 1A. In
particular, therapeutic agents may become trapped in microcavities
formed by the copolymers. The domains possibly form because of
thermodynamic forces and chemical associations between the blocks
force the blocks to associate. This phenomenon may advantageously
be exploited to make materials with enhanced properties for
carrying and releasing therapeutic agents.
Embodiments herein include, for example, copolymers having blocks
that have different glass transition temperatures (Tgs). Blocks
with significantly different glass transition temperatures
typically have the chemical properties that result in the creation
of domains. Further, association of a therapeutic agent with the
blocks may be accomplished with Tgs that are at least about 30, 50,
or 70.degree. Celsius (C.) different, or within subranges of these
specific ranges. Moreover, the combination of blocks may be made to
have an average Tg that is comparable to a physiological
temperature of a patient that receives an implant that has such a
copolymer. Thus, a copolymer may, in addition to one or more of the
other features already described, be made to with a composition of
monomeric units that have an average Tg that approaches a
physiological temperature of about 37.degree. C. Calculation and
determination of Tg is discussed in more detail, below.
Without being bound to a particular theory, the formation of blocks
may contribute to some of the properties of polymers described
herein. Referring to FIG. 1A, a copolymer 301 is depicted with
monomeric units 300 and having a Tg that is relatively low compared
to higher Tg monomeric units 302. The monomeric units are reacted
to form copolymers that may include blocks. Low Tg monomeric units
300 and high Tg monomeric units 302 may tend to form domains 303
and 304, respectively. As discussed below, describing monomeric
units as having a Tg that is equal to the Tg of the homopolymer
formed by such a monomeric unit provides some useful approximations
for properties of copolymers 301 and domains such as 303, 304.
Referring to a domain such as 303, 304 as having a Tg that is equal
to the Tg of the homopolymer formed by such a monomeric unit also
provides some useful insights. In a general perspective, glass
transition temperature (Tg) of a polymer depends on chain geometry,
chain flexibility and molecular aggregates. Domains in a polymer
have an influence in Tgs since domains will impact on chain
geometry, chain flexibility and molecular aggregates.
FIG. 1B shows a single copolymer 301 with low Tg domains 303 and
high Tg domains 304, with the high Tg domains 304 being more
ordered, particularly at a temperature below Tg for the high Tg
domains 304 and above the low Tg domains 303. Therapeutic agent 306
forms an association with domains 304. Such associations may be
driven by, e.g., ionic, polar, or hydrophobic-hydrophilic
interactions. As the ambient temperature is increased to approach
the Tg of monomeric units 302, the domains 304 are expected to have
more mobility and to release therapeutic agent 306 more
readily.
FIG. 1C shows copolymer 301 with low Tg domains 303 and high Tg
domains 304. The conformation of copolymer 301 entraps therapeutic
agent 308. Such a conformation might be achieved in a liquid or in
a solid, e.g., a polymeric layer. A liquid may include, e.g., a
melt or a composition containing water or an organic solvent.
FIG. 1D shows a composition 310 comprising multiple copolymers 301.
Such a composition could be, for instance, a liquid or a solid,
e.g., a layer. Domains 304 tend to form associations with each
other that allow for binding events or other associations to occur
between domains 304 and therapeutic agent 306. Alternatively,
domains 304 may form conformations that have microcavities
containing therapeutic agent 308. Such microcavities might form as
a result of the domains associating with, and packings around
therapeutic agents 308. Alternatively, a stiffness of domains 304
may create packing inefficiencies that are microcavities that may
subsequently be occupied by therapeutic agent 308.
Glass Transition Temperature and Polymer Terminology
Certain embodiments of copolymers described herein are related to
the property referred to as Tg. Tg is the temperature at which an
amorphous polymer (or the amorphous regions in a partially
crystalline polymer) changes from a hard and relatively brittle
condition to a viscous or rubbery condition. Glass transition
temperatures may be measured by methods such as differential
scanning calorimetery (DSC) or differential thermal analysis. Other
methodologies include volume expansion coefficient, NMR
spectroscopy and refractive index. Tg is a property of a
polymer.
A polymer is a molecule composed of repeated subunits. Each subunit
is referred to herein as a monomeric unit. Polymers of only a few
monomeric units are sometimes referred to as oligomers. A monomeric
unit may be the reaction product of a reactive monomer, but is not
limited to that meaning. Reactive monomers are reacted to form
polymers of monomeric units. The term polymer includes the meanings
of homopolymer, copolymer, terpolymer, block copolymer, random
copolymer, and oligomer. FIG. 2 shows examples of monomeric units,
and also indicates the Tg of homopolymers formed from such units.
Tgs for other homopolymers are: polybutylacrylate -49.degree. C.,
poly(tert-butyl methacrylate 107.degree. C., poly(butyl
methacrylate-co-isobutyl methacrylate) 35.degree. C., poly(butyl
methacrylate-co-methyl methacrylate) 64.degree. C., polyethyl
acrylate -23.degree. C., poly(2-ethylhexyl acrylate) -55.degree.
C., and poly(2-ethylhexyl methacrylate) -10.degree. C. The Tgs for
homopolymers are known to persons of ordinary skill in these arts
and are readily available from public sources, e.g., from the
ALDRICH catalog, polymer encyclopaedias, and the Polysciences Inc
Polymer & Monomer Catalog. And, for example, the U.S. Pat. No.
6,653,426 provides other details.
Some embodiments herein are directed to copolymers having certain
Tg values or averages. Unless otherwise specified, the average Tg
values are to be calculated on the basis of weight of the monomer
units. An alternative method is to calculate an average by molar
weight. The Tg for a homopolymer varies with MW until about 20,000,
so that a Tg for a homopolymer is customarily considered its Tg at
or above about 20,000 MW. This procedure may be used to calculate
the average Tg for a composition of monomeric units that are
disposed in a copolymer.
Other aspects of polymers relate to calculating the average polymer
weight. One such method is the weight average molecular weight,
which is calculated as follows: weigh a number of polymer
molecules, add the squares of these weights, and then divide by the
total weight of the molecules. The number average molecular weight
is another way of determining the molecular weight of a polymer. It
is determined by measuring the molecular weight of n polymer
molecules, summing the weights, and dividing by n. The number
average molecular weight of a polymer can be determined by, e.g.,
osmometry, end-group titration, and colligative properties.
A polymer may include a block. A series of identical monomeric
units joined together forms a block. A polymer may have no blocks,
or a plurality of blocks. Blocks from a group of polymers or from
one polymer may become associated with each other to form domains.
Thermodynamic forces can drive the formation of the domains, with
chemical attractions between the blocks contributing to the driving
force. For example, some blocks may tend to become associated with
each other as a result on ion-ion interactions or
hydrophobic-hydrophillic forces. Thus, in some conditions, a
composition of polymers having hydrophillic blocks and hydrophobic
blocks could be expected to form domains having hydrophobic blocks
and domains having hydrophilic blocks. A copolymer is a polymer
having at least two different monomeric units. Some copolymers have
blocks, while others have random structures, and some copolymers
have both blocks and regions of random copolymer bonding.
Copolymers may be made from reactive monomers, oligomers, polymers,
or other copolymers. Copolymer is a term that encompasses an
oligomer made of at least two different monomeric units. Reactive
comonomer is a term that may include more than two monomers.
Polymers, Tg, and Copolymers with Monomeric Units having a
Predetermined Difference in Tg
Certain embodiments herein relate to copolymers formed from
monomeric units that form homopolymers that have Tgs that have a
selected difference between them. Monomeric units are sometimes
referred to herein as having a Tg, by which is meant the Tg of the
homopolymer formed of the monomeric unit. Without being bound to a
particular theory of operation, the predetermined differences set
forth herein are believed to contribute to domain formation so that
certain desirable polymeric properties are enhanced. One such
property is enhanced association of therapeutic agents with the
domains. The domain-domain interactions may create small microvoids
for therapeutic agents, or may form chemical associations with the
therapeutic agents, which can be bonding associations or
electrostatic interactions.
Suitable predetermined Tg differences between monomeric units
include at least about 30.degree. C., at least about 50.degree. C.,
and at least about 70.degree. C. Other suitable differences in
monomeric units Tgs are in the range of about 30.degree. C. to
about 500.degree. C., about 50.degree. C. to about 300.degree. C.,
and about 70.degree. C. to about 200.degree. C. Persons of ordinary
skill in these arts, after reading this disclosure, will appreciate
that all ranges and values within these explicitly stated ranges
are contemplated.
Tg is an indirect and approximate indication of mobility of blocks
or domains of a composition of copolymers. For copolymers having a
non-covalent chemical or physical association with an agent, a
greater mobility, or lower Tg, would be expected to result in a
faster release of the agent. Other factors that affect release are
the size of the agent, its chemical characteristics, and the extent
of its association with the polymers around it. Some chemical
characteristics are, for example, hydrophilicity, shape/size,
presence of charges, and polarity. The most desirable rate of
release of an agent, however, is highly dependent on the
application. Some situations require a quick release, some require
a sustained release, and some require a quick burst, followed by a
sustained release. Further, a plurality of agents may be associated
with a polymer, or a layer, or a coating, so that the Tgs are
adjusted to reflect the chemistries of the agents.
When polymers are deposited in layers, the rate of release from the
layer is believed to be at least partially dependent on the size of
the domains, with smaller domains releasing agents more quickly
than larger domains. Alternatively, it may be that the domains have
irregular shapes and orientations that create microcavities. Then,
larger domains could pack less efficiently into the layer so as to
affect the quality of the microcavities. The microcavities may
receive the therapeutic agent, which migrates through the layer to
be released. Alternatively, it may be that the domains have
irregular shapes and orientations that cause them to fold into
three dimensional shapes in a melt or in a solution so as to create
microcavities in the folded shape that receive the therapeutic
agent. For all of these reasons, it is useful to be able to make
polymers, e.g., copolymers, from monomeric units having
predetermined differences in Tgs. Further, these considerations
point to the advantages of having copolymer systems that can be
adjusted to have Tgs within certain ranges.
While recognizing that a significant factor to control agent
release is to achieve a particular average Tg for agent-release
applications in (or on) a patient's body, the embodiments herein
describe a significant advance with respect to control of agent
release and elution based on the chemical composition of different
monomer units of a copolymer and their corresponding Tgs. This
sophisticated use of copolymer design goes far beyond recognition
of the significant aspect of agent release from a polymer that can
be achieved by choosing polymers having Tgs above or below a
certain value.
In addition to choosing a predetermined Tg differences for
monomeric units in a copolymer, other embodiments relate to
choosing sets of monomeric units with certain Tgs relate to the
average Tg of the set. In some embodiments, it is advantageous to
choose a particular average Tg. For instance, polymeric implants
loaded with a therapeutic agent can be made with polymers or
copolymers having a Tg that is close to a physiological
temperature. The Tg of the monomeric units in a polymer provides an
approximation of the Tg of the resultant polymer. Thus, a weighted
Tg average of a composition of monomeric units may be chosen for
making a copolymer having desired properties. Alternatively, other
applications call for an average Tg that is suitable to achieve a
change at a temperature for that application, e.g., movement form
cryostorage to superheated steam, from CO.sub.2 storage to oven,
from freezer to boiling, from a cooler to a hot water bath, and so
forth. Weighted Tg averages for copolymers and polymers as set
forth herein include from about -200.degree. C. to about
500.degree. C., from about -80.degree. C. to about 250.degree. C.,
from about -20.degree. C. to about 100.degree. C., from about
0.degree. C. to about 40.degree. C. Persons of ordinary skill in
these arts, after reading this disclosure, will appreciate that all
ranges and values within these explicitly stated ranges are
contemplated.
Persons of ordinary skill in these arts are acquainted with a wide
variety of polymers, reactive monomers, and functional groups.
Examples of polymers include polyacrylic acid, polyacrlonitrile,
polyallyamine, polyacrylates, polybutyl acrylate,
polymethylmethacrylate, polyalkyl acrylates, polyalkyl
methacrylate, polybutadiene, polycarbomethylsilane, poly(carbonate)
urethane; polydimethylsiloxane, polyethylene, polyethylene glycol,
polypropylene glycol, poly(ether) urethane, polyurethane, polyvinyl
chloride, polyvinyl alcohol, polymaleic anhydride, cellulose
nitrate, carboxyl methyl cellulose, dextran, dextran sulphate,
polypropylene, polyesters, polycarbonates, polyethers, polybutenes,
polymaleic acid, fluoropolymers, unsaturated polymers,
polyisoprene, polymelamine, polysulphones, polyureas, biological
polymers, proteins, gelatin, collagen, elastin, and copolymers and
terpolymers thereof. Monomeric units and reactive monomers
associated with these monomeric units are known to persons of skill
in these arts.
Examples of monomeric units include butyl acrylate, methyl
methacrylate, butyl methacrylate, hydroxyethyl methacrylate,
acrylic acid, methacrylate acid, polyethylene glycol, polyethylene
glycol monomethacrylate, polyethylene glycol dimethacrylate,
polypropylene glycol diglycidal ether, polyethylene glycol
diglycidyl ether, isocyanatoethyl methacrylate,
N-acryloxysuccinimide, glycidyl methacrylate, hexamethylene
diisocyanate, acrolein, crotonaldehyde, glycerol monomethacrylate,
heparin methacrylate, methacryloyloxyethyl phosphorylcholine and
combinations thereof. Reactive monomers associated with these
monomeric units are known to persons of skill in these arts.
In some embodiments, reactive monomers may be bi-functional
monomers, while in other embodiments the monomers may be
tri-functional or multifunctional monomers. In further embodiments,
the reactive monomers comprise a combination of bi-functional,
tri-functional and/or multifunctional monomers.
Examples of functional groups include hydroxyl, amine, carboxylic,
aldehyde, ketone, thiol, allyl, acrylate, methacrylate, butyl
acrylate, isocyanate, epoxide, azides, aziridines, acetals, ketals,
alkynes, acyl halides, alky halides, hydroxy aldehydes and ketones,
allenes, amides, bisamides, amino acids and esters, amino carbonyl
compounds, mercaptans, amino mercaptans, anhydrides, azines, azo
compounds, azoxy compounds, boranes, carbamates, carbodimides,
carbonates, diazo compounds, isothionates, hydroxamic acid, hydroxy
acids, hydroxy amines and amides, hydroxylamine, imines, lactams,
nitriles, sulphonamides, sulphones, sulphonic acids and
thiocyanates.
Polymers, e.g., copolymers may be made by a variety of processes
known to persons of ordinary skill in these arts. Polymers and
copolymer may be made from, e.g., reactive monomers, polymers,
oligomers, copolymers, and combinations thereof, using various
reaction schemes. Examples of reaction schemes include free radical
polymerization, addition polymerization, condensation
polymerization, electrophile/nucleophile reactions, urethane
reactions, and combinations thereof. Reactions that form a polymer
may, in some cases, be initiated by an initiator. Examples of
polymerization initiators include, for example, thermal initiators,
UV initiators, free radical initiators, electromagnetic initiators,
polymerization catalysts and combinations thereof. Free radical
initiators include, for example, peroxides.
Some embodiments relate to polymers, e.g., copolymers, that have a
reactive functional group. Methods of making such polymers include,
e.g., using reaction schemes that create the bonds that unite the
monomeric units without forming covalent bonds with the reactive
functional groups. Another method is to derivatize a polymer after
it has been formed by using additional chemical reactions to join a
functional group to the polymer. Some schemes are a combination of
these methods that involve reacting a functional group on a polymer
to add or create a new reactive functional group. Many such
reactions are known to persons of ordinary skill in these arts.
Certain embodiments relate to making copolymers from a melt of
reactive monomers, or other reactive components. A melt of
materials is a composition of those materials that has little or no
solvent or diluents, and is a flowable, albeit sometimes highly
viscous, liquid. The high concentration of reactable components in
the melt may be advantageous in some circumstances, e.g., by
helping to form copolymers having a molecular weight that is
relatively higher than more dilute compositions. A melt with less
than about 5% solvent by volume would be deemed a melt, as that
term is used herein. A pure melt is a melt with essentially no
solvent or diluents.
Some embodiments relate to polymers, e.g., copolymers, having a
certain molecular weight (MW) or MW range. Generally, polymers have
a distribution of molecular weights corresponding to a collection
of polymer chains within the composition. A polymer's MW is usually
related to its mobility, its conformation, and other polymeric
properties. Some embodiments may have an average molecular weight
of at least 2,500 to engender the desired polymer properties. Other
average MWs and ranges of average MWs are at least 5,000, at least
25,000, at least 100,000, at least 500,000, between 1,000 and
10,000,000, and between 2500 and 1,000,000. A person of ordinary
skill in these arts will appreciate that all MW values and ranges
within these explicit limits and ranges are contemplated.
Some polymers are predominantly hydrophilic. Such polymers, when
wetted with water, have a slippery feel to them that can be
characterized as lubricious. Lubricity is a quality that is useful
in some devices, and in some medical device surfaces. A lubricious
surface, for example, lends itself to ease of implantation because
the surface can contact tissue in a patient with a minimum of
friction.
Polymers for medical implants are preferably biocompatible with the
patient that receives them. Ordinary artisans recognize the quality
of biocompatibility appropriate for a particular situation. For
example, the presence of toxic leachables in an implant makes
materials non biocompatible in most situations. Further, a property
of little or essentially no immunogenicity is recognized as being
appropriate for some applications.
The Examples provide various embodiments of polymers described
herein. A person of skill in these arts, after reading the
Examples, will be able to adapt and apply the methods taught in the
examples to practice the various embodiments of making and using
copolymers described herein. Example 1 describes preparation of
copolymer with monomeric units of predetermined difference in Tg,
specifically, 2-Hydroxyethyl methacrylate-co-butyl
acrylate-co-butyl methacrylate. Butyl acrylate forms a homopolymer
of Tg -54.degree. C., 2-Hydroxyethyl methacrylate forms a
homopolymer of Tg 57.degree. C. and butyl methacrylate forms a
homopolymer of Tg 20.degree. C.; the reactive monomers were mixed
at a weight ratio of 10:11:29, respectively. Example 2 shows an
alternative embodiment using the same monomeric units at different
weight ratios. Examples 3-6 present other alternative embodiments,
wherein copolymers have monomeric units wit certain Tg
differences.
Example 6, which describes making of heparin
methacrylate-co-2-hydroxyethyl methacrylate-co-butyl
acrylate-co-butyl methacrylate, shows how a chemically bound
anti-coagulant may be incorporated into a copolymer as one of the
monomeric subunits. Heparin was decorated with a reactive
functional unit that was polymerizable with reactive monomers. The
heparin thus incorporated is highly stable. Other anticoagulants
may be incorporated in a similar fashion. Such anticoagulants
include, e.g. warfarin, hirudin, dextran sulphate, hyaluronic acid,
and derivatives thereof.
Example 9 shows a preparation of polymers (e.g., copolymers) with
reactive functional groups for subsequently forming covalent bonds.
In Example 9, a copolymer was decorated with a reactive monomer.
The reactive monomer is available for subsequent polymerization and
crosslinking with other polymers. The particular example used was
poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate-methacrylate.
Other Examples show this copolymer in use. Example 18 describes a
copolymer having reactive functional groups that are able to react
with nucleophiles to form a covalent bond. The copolymer has
isocyanate groups that may subsequently form crosslinks with other
polymers having suitable reactive functional groups. Example 19
describes a copolymer having reactive functional groups that are
able to react with electrophiles to form a covalent bond. Example
19 further describes how copolymers with reactive electrophiles may
be reacted with polymers having reactive nucleophiles to form
covalent bonds between them and thereby crosslink the polymers.
Formation of Layer(s)
Polymers, e.g., copolymers, taught herein may be used to form a
coating. Polymeric coatings are formed on an object. In contrast,
other polymeric constructs, e.g., sheaths, sleeves, membranes, and
molded objects, can be manufactured separately from a particular
device. Consequently, coatings are distinct from other types of
polymeric construct. For example, a sleeve, sheath, or membrane
requires a certain minimum of mechanical robustness so as to
maintain its identity before being associated with an object.
Further, a process of coating creates an intimacy of contact
between the coating and the device that is often desirable; for
this reason, some processes involve coatings instead of other
manufacturing procedures. Moreover, some processes of coating an
object such as spraying or dipping create physical properties or
processing opportunities that are not available in other processes.
Further, teachings that are related to polymeric devices may not be
applicable for coatings because of these differences.
It is recognized, however, that a coating can have variable
characteristics. Thus a coating may be discontinuous with a surface
at some points and still retain its characteristic as a coating.
Coatings may also be formed of a single layer, or a plurality of
layers. Coatings, and layers, can have a variable thickness,
variable composition, variable chemical properties. Coatings, and
layers, may cover all or a portion of a surface. Layers may, e.g.,
be superimposed upon other layers to create a coating.
Processes for forming a layer on an object, e.g., a medical device,
may include applying a composition to a device by spraying, or by
dipping the device into a composition for forming a polymeric
layer. These and other methods are generally known to persons of
ordinary skill in these arts. Polymers taught herein may be formed
in layers upon a medical device, including a layer that covers all
of a device, a layer that covers a portion of the device, and
layers upon other layers. Layers that contact each other may be
crosslinked to each other, e.g., by covalent crosslinks between
polymers in the layers.
Some embodiments of layers are formed by preparing a composition of
polymers, e.g., copolymers, and applying them to a surface. Other
embodiments are layers formed by applying a composition of reactive
monomers to a device or a layer and initiating polymerization to
form a layer from the reactive monomers. Similarly, polymers may be
applied to a device or layer and reacted there to form a layer.
Layers may also be crosslinked together. One method is to apply a
first layer that has a first set of reactive functional groups, and
to apply a second layer that has reactive functional groups that
has a second set of reactive functional groups that form covalent
crosslinks with the first set of functional groups. The first layer
and second layers may be applied in any order, e.g., starting with
the first, then the second, or vice versa. Additional layers may be
similarly formed and used.
Layers may be made from a single type of polymer, a plurality of
polymers, a single type of reactive monomer, a plurality of
reactive monomer types, or a combination thereof. For example, a
single type of copolymer could be used, or a plurality of
copolymers, each prepared separately, could be used. Or a single
reactive monomer could be mixed with reactable or unreactable
polymers.
Some layers are useful for providing a base layer that contacts a
device and serves to anchor subsequently applied layers. For
example, a first layer with reactive functional groups may be
applied to a device, and a subsequent layer may be crosslinked to
the base layer. A therapeutic agent could be associated with the
base layer, the subsequently applied layer, or both. A layer that
overlays a layer that has a therapeutic agent can usefully serve to
slow the release of the therapeutic agent in the underlying layer.
Such layers may or may not be crosslinked together. Layers may have
a single type of functional group, or a plurality thereof, and may
be reacted with other layers having the same, similar, or
complementary reactive functional groups. For example a layer
having reactive monomers may be reacted with another layer having
the same or difference species of reactive monomers. A polymer in a
layer may have a single type of reactive functional group, or a
plurality of types.
Some layers are formed by chemically reacting other layers, e.g.,
using surface chemistry. For example, a layer may have reactive
functional groups that are exposed to a chemical composition of
polymers or non-polymers that have a functional group to react
thereto. Or, for example, a layer may be exposed to reactive
functional groups that are reactable thereto. For example, a layer
may be exposed to a composition of light-activatable molecules that
are triggered by light to react with the layer. Or a layer having
nucleophilic groups may be exposed to a composition of molecules
having electrophilic groups that react with the nucleophiles. For
instance, Example 12 describes a layer that is reacted with a
heparin azide.
Any of these layers may be associated with a therapeutic agent, and
may be formed on a medical device with or without the presence of a
therapeutic agent. A therapeutic agent may be associated with the
components of the layer, before, during, or after its application
to a device. Thus a layer and a therapeutic agent may be
essentially simultaneously applied to a device. Such an application
has some advantages, e.g., for ease of manufacturing. For example,
a copolymer may be associated with a therapeutic agent and the
copolymer-therapeutic agent association may be applied to a device.
Or, for example, a therapeutic agent may be part of a composition
that is applied to a surface that is subsequently activated to form
new copolymers. As indicated above, certain copolymers may
advantageously be combined with a therapeutic agent to achieve
delivery of the agent.
Therapeutic agents may be associated with a copolymer before the
copolymer is applied to a device. The copolymer may be prepared and
then exposed to a solution containing a solvent for the agent. The
agent and the copolymer are allowed to interact, and the agent
becomes associated with the copolymer, possibly by association with
domains or microcavities, as discussed above. Alternatively, a
therapeutic agent may be added to a melt that is used to form the
copolymer.
Or the therapeutic agent may be exposed to a copolymer at
essentially the same time that the agent and the copolymer are
essentially simultaneously applied to a device. The agent and the
copolymer could be in the same or difference solvent, or
alternatively, in the same of different non-solvents that are
carrier agents. The application of one or both of the copolymer and
the agent in a nonsolvent would affect the resultant layer. For
example, a copolymer deposited in a solvent and an agent deposited
in a nonsolvent for the copolymer could help to form reservoirs,
e.g., microcavities, for entrapping the therapeutics agent.
Nonsolvent and solvent are terms used somewhat broadly and include
their strict meanings and also as including mixtures diluted with
other substances. These terms are applied in light of a particular
application, and are sometimes given meanings that indicate
relatively good or relatively poor solvency.
Therapeutic agents may be associated with a layer after the layer
is applied to a device. One method is to expose the layer to a
mixture containing the agent. The mixture may include a relatively
good solvent for both the agent and the layer so that the layer is
swelled and the agent migrates therethrough. When the solvent is
removed, the agent is left in the layer. Examples 15 and 16
demonstrated this method, and was shown to be effective for
copolymers as taught herein.
The Examples provide various embodiments of layers taught herein. A
person of skill in these arts, after reading the Examples, will be
able to adapt and apply the methods taught in the Examples to
practice the various embodiments of making and using layers and
other embodiments taught herein. Example 8 describes application of
a layer to a medical device, and uses a stent as an example. The
copolymer of Example 1 was applied to a stent essentially
simultaneously with a therapeutic agent using a spray process. The
agent and the copolymer were both in the same organic solvent.
Paclitaxel was effectively loaded using this method.
Spraying was also used in other Examples. The layer thus formed was
then available for use as an implant, or as a base for the addition
of subsequent layers.
Example 10 shows methods for applying polymers (e.g., copolymers)
as taught herein onto medical devices. The methods may involve
forming a plurality of layers, with a first layer being covalently
crosslinked to another layer simultaneously with, or after, the
deposition of other layers. A stainless steel coronary stent was
used for illustrative purposes. In this embodiment, a first
reactive polymeric layer was deposited, followed by a second
reactive polymeric layer containing a therapeutic agent, and an
initiator that works spontaneously was used. Both polymer layers
had methacrylates as the reactive functional groups for the
crosslinking of the layers to each other. This Example further
showed mechanical properties suitable for use on expandable medical
devices such as stents or balloons. Paclitaxel was effectively
loaded and released. Example 11 is an alternative embodiment
demonstrating the use of a thermal initiator.
Example 13 shows the formation of a plurality of layers on a
medical device and methods of crosslinking the layers. A first
layer had a first reactive monomer that was used to form covalent
bonds with a composition of reactive monomers that were polymerized
with the first reactive monomer to simultaneously form a second
layer and crosslink the second layer to the first layer. The
therapeutic agent was associated with the outermost layer, but
could have been associated with the innermost layer, or both
layers. The therapeutic agent was, in this case, loaded into the
second layer by polymerizing the second layer in the presence of
the agent. This method effectively loaded the agent, e.g., see FIG.
7. Example 14 is an alternative embodiment of this method that
showed the use of another scheme for initiating polymerization, in
this case, in the presence of a therapeutic agent. Example 16 is
similar to Example 13, but the therapeutic agent was not introduced
until after the deposition of the layers. This method effectively
loaded the agent.
Example 17 shows a method for coating a medical device with a first
layer being a copolymer having reactive functional group
crosslinked to a second layer. The first layer anchored the second
layer, which contained a therapeutic agent. The agent was applied
essentially simultaneously with the second layer. Initiation of
polymerization of the second layer was performed after deposition
of the second layer components, by use of a thermal initiator and
application of heat. Alternative initiators could be used.
Initiation and essentially simultaneous polymerization of the
second layer could be achieved by applying an initiator with the
second layer components and initiating it at that time, e.g., by
applying heat to a thermal initiator, UV to a UV initiator, or by
use of a spontaneous initiator.
Example 18 demonstrates the application of a plurality of layers by
using a reactive copolymer in one of the layers. In this case, the
layer applied to the device had reactive functional groups capable
of forming covalent bonds with nucleophiles. A composition of the
reactive copolymer was sprayed onto the surface to form a first
layer, and then covered with a layer of a polymer that was reacted
to the first layer. The polymer was chosen to be hydrophilic and
lubricous, but other polymers with suitable chemical groups for
reacting with the first layer could have been chosen. One
embodiment was performed without a therapeutic agent and another
embodiment was performed with an agent; in this case, the agent was
added after the second layer was formed. These methods were
successful. Similarly, other initiation and polymerization schemes,
as taught herein, could have been used.
Example 20 shows the formation of a plurality of layers on a
device. In this embodiment, one of the layers had a therapeutic
agent and the other layer did not. The layer without the agent was
applied to slow release of the agent in the layer where the agent
is initially disposed. The second polymer layer helped to control
the diffusion of the active agent into the bulk. Example 21 was
performed with similar methods, but the two layers are crosslinked
together. FIG. 9 shows the release profiles for these systems.
Referring to FIG. 3, polymeric network coating 100 comprises a
first polymeric layer 101 and reactive monomers that can react with
at least first polymeric layer 101 to form a second layer 102. In
some embodiments, the polymeric network 100 comprises domains or
microcavities 104 located within the second layer 102 of the
polymeric network 100. In some embodiments, therapeutic agents 106
are incorporated into the polymeric network 100. In one embodiment,
active agents 106 are disposed in micro cavities 104 of second
layer 102. In some embodiments, the size of the domains or
microcavities may be about the size, e.g., the molecular weight or
dimensions, of the active agents. The size and shape of the micro
cavities 104 can also be varied by employing a mixture, or ratio,
of different reactive monomers. In some embodiments, polymeric
layer 101 comprises a polymer that is non-thrombogenic and/or
anti-thrombogenic. In general, the reactive monomers should be
selected so that the resulting polymeric network 100 is suitable
for medical applications.
In some embodiments, active agents 106 can be water soluble, while
in other embodiments active agents 106 can be soluble in organic
solvents. In further embodiments, polymeric network 100 can
comprise a mixture of water soluble and organic solvent soluble
active agents. One of ordinary skill in the art will recognize that
additional active agents are within the scope of the present
disclosure.
In some embodiments, active agents 106 are disposed in the cavities
104 of the polymeric network 100. In one embodiment, active agents
106 can be disposed into the cavities 104 of the polymeric network
100 by dissolving the active agents 106 in a solvent and then
coating the polymeric network 100 with the active agent/solvent
mixture. Once the solvent evaporates, the active agents 106 can be
disposed in the cavities 104 of polymeric network 100.
Alternatively or additionally, the active agents 106 may be
disposed into the cavities 104 of polymeric network 100 by mixing
the active agents 106 with the reactive monomers so that the active
agents 106 become disposed in the second layer 102 of polymeric
network 100 as the second layer 102 is formed.
In some embodiments, active agents 106 can be released from the
polymeric network 100 through micro cavities 104 to contact a site
within a patient. In general, the release profile for a particular
active agent can be influenced, or varied, by the size and quantity
of active agents 106 relative to the size, composition and shape of
micro cavities 104 of polymeric network 100. As described above,
micro cavity size and shape can be influenced, or varied, by the
particular selection of reactive monomers and the relative ratios
of the different monomers used to form the polymeric network
100.
As shown in FIG. 4, in some embodiments, the polymeric network 100
is coated, or formed, onto the outside surface 201 of a medical
device 202. In some embodiments, the polymeric network 100
comprises micro cavities 104 in which active agents 106 are
disposed. The medical device can be any medical device in which it
would be beneficial to have active agents 106 releasing out of
medical device during use. Examples of suitable medical devices
include catheters, guide wires, vascular grafts, stents, stent
grafts and the like.
In some embodiments, to form coated medical device 200, first
polymeric layer 101 is applied to outside surface 201 of medical
device 202. As noted above, first polymeric layer 101 should be
selected so that first polymeric layer 101 adheres to outside
surface 201 of medical device 202. First polymeric layer 101 can be
contacted with a reactive monomer composition. The reactive monomer
composition can comprise reactive monomers, and optionally
polymerization initiators, polymerization catalysts and active
agents 106. The reactive monomer composition can react with first
polymer layer 101 to form second layer 102 of polymeric network 100
on medical device 202. In some embodiments, active agents 106 can
be introduced into polymeric network 100 as polymeric network 100
is formed by mixing active agents 106 with the reactive monomer
composition.
In other embodiments, polymeric network 100 can be formed and
active agents 106 can be disposed into micro cavities 106 of
polymeric network 100 by coating polymeric network 100 with a
solvent/active agents mixture. Once the solvent has evaporated,
active agents 106 can be disposed in micro cavities 104 of
polymeric network 100. In embodiments where active agents 106 are
introduced into the cavities 104 of polymeric network 100 through a
solvent, any solvent that can deliver the active agents 106 and
does not degrade or react with active agents 106 can potentially be
used. In general, the choice of a particular solvent will be
determined by specific active agents 106 being employed. Suitable
solvents include, for example, water, alcohols, ethers, acetone,
methyl ethyl ketone, and combinations thereof.
Additional embodiments are the introduction of a copolymer, layer,
coating, or device as taught herein into a patient, mammal, human,
animal, or in vitro system. Embodiments having a therapeutic agent
may release the agent to accomplish a therapy for treatment of a
medical condition. Some embodiments herein refer to layers
associated with a medical device. Alternatively, the layers may be
associated with a surface of a medical device, or a portion
thereof. Further, a medical implant is a type of device that is
implanted into a patient or placed upon a patient. A pacemaker and
a catheter are implants, as would be a nicotine patch.
Medical devices include, for example any device that is
implantable, used topically or comes in contact with living tissue.
The devices could be made from plastic, such as catheters; from
metals, such as guide-wires, stents, embolising coils; from
polymeric fabric, such as vascular grafts, stent grafts; other
devices include heart valves, implantable cardiovascular
defibrillators, pacemakers, surgical patches, patches, wound
closure, micro-spheres, biosensors, sensors (implantable, ex-vivo
and analysers) ocular implants and contact lenses; medical devices
that are made from ceramic, glass; tissue engineering scaffolds.
Medical devices are also discussed in, e.g., U. S. Pat. Nos./patent
application Ser. Nos. 5,464,650; 5,900,246; 6,214,901; 6,517,858;
US 2002/0002353; and in patent applications WO 01/87342 A2; WO
03/024500.
The application of a coating to a medical device may be adapted to
the particular circumstances for that device. For example, with
regards to thickness, the particular application may indicate what
is suitable. A stent, for example, must be threaded through a
tortuous system of blood vessel to reach its pint of application in
a patient. So a coating on the stent should have suitable physical
properties and thickness. The thickness of the polymeric layer is
of a range that a therapeutic dose is delivered without impeding
the effects of the drug and the performance of the medical device,
for example a stent may have a polymeric layer in the range of,
e.g., about 2 .mu.m to about 150 .mu.m, or between about 1 and
about 300 .mu.m. Other ranges for other medical devices may vary
widely, but some ranges are less than 3 mm, less than 1 mm, less
than 0.1 mm, less than 0.01 mm, 1-100 .mu.m, 10-1000, .mu.m,
1-10,000 .mu.m, and 10-500 .mu.m; persons of ordinary skill in
these arts will realize that all values and ranges within these
explicit ranges are contemplated, and that other ranges may be
suited as depending upon the device and/or application.
Some devices and applications require an expandable or a flexible
layer. As set forth in the Examples, embodiments herein are
provided that provide for flexibility and/or for expandability.
With respect to a stent, most designs of stents require a step of
expansion upon deployment in a patient. A layer that is expandable
to accommodate the stent deployment is advantageous. With respect
to a medical balloon, its use in the patient requires a step of
expansion; accordingly, a coating on such a balloon may
advantageously be made so as to accommodate that expansion.
Other Aspects of Material Formation
Polymers, e.g., copolymers, as described herein may also be used to
form materials that are not layers or are not coatings, and
embodiments set forth herein as layers may be applied or adapted as
needed to make other materials. For example, a copolymer as taught
herein may be used in a process to make a sheet, membrane, sheath,
plug, implant, or a medical device. Many polymer processes are
known in these arts for making such objects, e.g., molding,
extrusion, and casting. Moreover, delivery devices for a
therapeutic agent may be formed using a polymer as described
herein, e.g., a pill, tablet, suppository.
Such constructs may be associated with a medical device to provide
desired mechanical properties, e.g., lubricity, stiffness,
flexibility, or expandability to provide a release of a therapeutic
agent.
Stents are a medical devices that provide a scaffolding to
physically hold open a tissue by deployment in a tissue; they are
have a first position that is collapsed for introduction into a
patient and a second position during deployment. The second
position is expanded relative to the first position. Embodiments
herein may be used with a stent or with a medical device that is
not a stent. An embodiment herein is a coating, composition,
polymer (e.g., copolymer) as taught herein that is associated with
at least a portion of a medical device, wherein that device does
not physically hold open a tissue by deployment in the tissue.
Another embodiment is a coating, composition, polymer (e.g.,
copolymer) as taught herein that is associated with at least a
portion of a medical device, wherein that device does not allow
passage of a fluid therethrough, e.g., a pacemaker or a pacemaker
lead.
An embodiment herein is a medical device, coating, or a composition
comprising a copolymer as taught herein that is associated with at
least a portion of an expandable portion of a medical device.
Another embodiment herein is a coating, composition, polymer (e.g.,
copolymer) as taught herein that is associated with at least a
portion of a medical device that is not expanded during use or
deployment of the device.
Therapeutic Agents
Materials set forth herein may be associated with therapeutic
agents, including drugs, imaging agents, diagnostic agents,
prophylactic agents, hemostatic agents, tissue engineering agents,
nitric oxide releasing agents, gene therapy agents, agents for
enhancing wound healing, and bioactive agents. A therapeutic agent
may be mixed with a polymer precursor that is in solution or
disposed in a solvent, and the polymer may be formed.
Alternatively, the therapeutic agent may be introduced after the
polymer is formed or at an intermediate point in the polymer
formation process. Certain embodiments include polymers that are
made in a first solvent and exposed to a second solvent that
contains the therapeutic agent so as to load the therapeutic agent
into the polymer. The term therapeutic agent is used to include,
for example, therapeutic and/or diagnostic agents, and/or agents
that are to be released from a coating.
Therapeutic agents include, for example, vasoactive agents,
neuroactive agents, hormones, growth factors, cytokines,
anaesthetics, steroids, anticoagulants, anti-inflammatories,
immunomodulating agents, cytotoxic agents, prophylactic agents,
antibiotics, antivirals, antigens, and antibodies. Other
therapeutic agents that can be provided in or on a coating material
in accordance with the present invention include, but are not
limited to, anti-thrombogenic agents such as heparin, heparin
derivatives, urokinase, and PPack (dextrophenylalanine proline
arginine chloromethylketone); anti-proliferative agents such as
enoxaprin, angiopeptin, or monoclonal antibodies capable of
blocking smooth muscle cell proliferation, hirudin, and
acetylsalicylic acid; anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine, and mesalamine;
antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin and thymidine kinase
inhibitors; anesthetic agents such as lidocaine, bupivacaine, and
ropivacaine; anti-coagulants such as D-Phe-Pro-Arg chloromethyl
keton, an RGD peptide-containing compound, a polylysine-containing
compound, heparin, antithrombin compounds, platelet receptor
antagonists, anti-thrombin, anti-platelet receptor antibodies,
aspirin, prostaglandin inhibitors, platelet inhibitors and tick
antiplatelet peptides; vascular cell growth promoters such as
growth factor inhibitors, growth factor receptor antagonists,
transcriptional activators, and translational promoters; vascular
cell growth inhibitors such as growth factor inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; cholesterol-lowering agents; vasodilating agents; and
agents which interfere with endogenous vasoactive mechanisms. Other
examples of therapeutic agents include a radiopharmaceutical, an
analgesic drug, an anesthetic agent, an anorectic agent, an
anti-anemia agent, an anti-asthma agent, an anti-diabetic agent, an
antihistamine, an anti-inflammatory drug, an antibiotic drug, an
antimuscarinic drug, an anti-neoplastic drug, an antiviral drug, a
cardiovascular drug, a central nervous system stimulator, a central
nervous system depressant, an anti-depressant, an anti-epileptic,
an anxyolitic agent, a hypnotic agent, a sedative, an
anti-psychotic drug, a beta blocker, a hemostatic agent, a hormone,
a vasodilator, a vasoconstrictor, and a vitamin. Other therapeutic
agents may be used, e.g., as set forth in U.S. patent application
Nos. U.S. 6,214,901; 6,673,385; and 2002/0002353.
In some embodiments, a therapeutic agent is covalently incorporated
into a layer. Example 10, for instance, shows a heparin azide that
is attached to a layer. Heparin is an anticoagulant with favorable
biomaterial properties. Alternatively, heparin macromers may be
used as monomeric units, as polymers, or to form polymers as
described herein. Heparin macromers are described in commonly owned
and assigned U.S. patent applications Ser. Nos. 10/179,453, filed
Jun. 26, 2002, and 10/750,706, filed Jan. 5, 2004, which are hereby
incorporated by reference herein. Other anticoagulants that may be
analogously used include, e.g., warfarin, hirudin, dextran
sulphate, hyaluronic acid, and derivatives thereof. Other
therapeutic agents may be used in conjunction with such
molecules.
Other therapeutic agents may be used in conjunction with such
molecules. Other examples of anti-platelets, anti-fibrin,
anti-thrombin, anti-coagulants include, sodium heparin, low
molecular weight heparins, heparinoids, argatroban, forskolin,
vapiprost, protacyclin and protacyclin analogues,
D-phe-pro-arg-chloromethyketone (synthetic anti-thrombin), other
synthetic anti-thrombin, synthetic thrombin inhibitors,
dipyridamole, glycoprotein IIb/IIIa platelet receptor antagonist
antibody, recombinant hirudin, and thrombin inhibitors such as
Anigiomax.TM.. Other examples of anti-platelets, anti-fibrin,
anti-thrombin, anti-coagulants include, sodium heparin, low
molecular weight heparins, heparinoids, argatroban,
forskolin,vapiprost, protacyclin and protacyclin analogues,
D-phe-pro-arg-chloromethyketone (synthetic anti-thrombin), other
synthetic anti-thrombin, synthetic thrombin inhibitors,
dipyridamole, glycoprotein IIb/IIIa platelet receptor antagonist
antibody, recombinant hirudin, and thrombin inhibitors such as
Anigiomax.TM.. Moreover, heparin, warfarin, hirudin, dextran,
dextran sulphate, hyaluronic acid, derivatives thereof, and other
anticoagulants may be used a releasable therapeutic agents. Other
examples of anti-platelets, anti-fibrin, anti-thrombin,
anti-coagulants include, sodium heparin, low molecular weight
heparins, heparinoids, argatroban, forskolin, vapiprost,
protacyclin and protacyclin analogues,
D-phe-pro-arg-chloromethyketone (synthetic anti-thrombin), other
synthetic anti-thrombin, synthetic thrombin inhibitors,
dipyridamole, glycoprotein IIb/IIIa platelet receptor antagonist
antibody, recombinant hirudin, and thrombin inhibitors such as
Anigiomax.TM..
Therapeutic agents include, for example, those as disclosed in U.S.
Pat. No. 6,214,901 to Chudzik et al., titled "Bioactive Agent
Release Coating". Additional embodiments of therapeutic agents, as
well as polymeric coating methods, reactive monomers, solvents, and
the like, are set forth in U.S. Pat. Nos. 5,464,650, 5,782,908;
5,900,246; 5,980,972; 6,231,600; 6,251,136; 6,387,379; 6,503,556;
and 6,517,858. The patents and patent applications EPO950386, WO
01/01890, WO 01/87342, U.S. 2002/0002353, and U.S. patent
applications Ser. Nos. 10/179,453, filed Jun. 26, 2002, and
10/750,706, filed Jan. 5, 2004, which are hereby incorporated by
reference herein.
EXAMPLES
The following materials were purchased from Sigma-Aldrich Company:
2-Hydroxyethylmethacrylate, butyl acrylate, butyl methacrylate,
benzoyl peroxide (40% wt. blend in dibutyl phthalate), 2-propanol,
petroleum ether (b.p. 100-120.degree. C.), N,N-dimethyl acetamide,
lauryl methacrylate, methoxy polyethylene glycol mono methacrylate
(M.W. 550), dimethyl sulphoxide, tetrahydrofuran, isocyanatoethyl
methacrylate, ethylene glycol dimethacrylate, benzoin methyl ether,
poly(vinylchloride-co-vinyl acetate-co-vinyl alcohol), dibutyl tin
dilaurate, polyvinyl pyrrolidone (average M.W. 1,300,000),
aminoethylmethacrylate hydrochloride.
2,2-azobis-(2-methylbutyronitrile) was purchased from Wako
Chemicals. Glycero mono methacrylate was purchased from Rohm GmbH.
Bis(4-t.butyl cyclohexyl)peroxydicarbonate (Perkadox 16) was
purchased from Akzo Nobel.
Example 1
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg: 2-Hydroxyethyl methacrylate-co-butyl
acrylate-co-butyl methacrylate
2-Hydroxyethyl methacrylate (11 g, 0.085 moles), butyl acrylate (10
g, 0.078 moles) and butyl methacrylate (29 g, 0.2 moles) were mixed
together. A 250 ml three-necked round bottom flask fitted with a
reflux condenser, thermometer and a nitrogen bleed was charged with
the above monomer solution and was heated to 80.degree. C. with
stirring. Polymerisation was initiated with the addition of
2,2'-azobis-(2-methylbutyronitrile)(0.8 g). The reaction was
allowed to proceed for 30 minutes, and then benzoyl peroxide (1.15
g)(40% wt. blend in dibutyl phthalate) was added. The reaction
proceeded for a further 60 minutes. The temperature of the reaction
was kept at 100.degree. C.+/-5.degree. C.
Upon cooling the above viscous mixture, 2-propanol (50 ml) was
added and then poured into petroleum ether (100-120.degree. C.)(800
ml) to precipitate the polymer. The precipitated polymer was washed
twice with 300 ml of petroleum ether. 2-Propanol (100 ml) was added
to dissolve the polymer with heating and stirring. Polymer was
concentrated to viscous slurry with evaporation of 2-propanol.
Water (1000 ml) was added to re-precipitate the polymer. After a
further 2 washings with water (1000 ml) the polymer was frozen and
then freeze dried. Yield=70% (32 g) Mw=44,939; Mn=13,291 Daltons;
Mw/Mn=3.375 (From GPC data).
Example 2
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg: 2-Hydroxyethyl methacrylate-co-butyl
acrylate-co-butyl methacrylate, Alternative Ratios and Weight
Averaged Tg
2-Hydroxyethyl methacrylate (15 g, 0.1 15 moles), butyl acrylate
(25 g, 0.195 moles) and butyl methacrylate (10 g, 0.07 moles) were
mixed together, polymerised to form a polymer, the polymer was
purified and dried, as described in Example 1. Yield=70% (32 g)
Mw=118,082; Mn=12,460 Daltons; Mw/Mn=9.47 (From GPC data)
Example 3
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg: Poly(hydroxyethyl
methacrylate-co-butylacrylate)
2-Hydroxyethyl methacrylate (20 g, 0.154 moles), butyl acrylate (30
g, 0.234 moles) and N,N-dimethylacetamide (DMA)(15 ml) were mixed
together. A 250 ml three-necked round bottomed flask fitted with a
reflux condenser, thermometer and a nitrogen bleed was charged with
the above momoner solution in DMA and was heated to 80.degree. C.
with stirring. Polymerisation was initiated with the addition of
2,2'-azobis-(2-methylbutyronitrile)(0.8 g). The reaction was
allowed to proceed for 30 minutes, and then benzoyl peroxide (115
g)(40% wt. Blend in dibutyl phthalate) was added. The reaction
proceeded for a further 60 minutes. The temperature of the reaction
was kept at 100.degree. C.+/-5.degree. C.
After cooling the above viscous polymer, was poured into water
(1000 ml) to precipitate the polymer. After a further 3 washings
with water (1000 ml) the polymer was frozen and then freeze dried.
The freeze dried polymer was then dissolved in 2-propanol (50 ml)
was added and then poured into petroleum ether at 100-120.degree.
C. (800 ml) to precipitate the polymer. The precipitated polymer
was washed twice with 300 ml of petroleum ether. 2-Propanol (100
ml) was added to dissolve the polymer with heating and stirring.
Polymer was concentrated to viscous slurry by evaporation of
2-propanol. Water (1000 ml) was added to re-precipitate the
polymer. After a further 2 washings with water (1000 ml) the
polymer was frozen and then freeze dried. Yield=35 g (70%)
Example 4
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg: Poly(hydroxyethyl methacrylate-co-lauryl
methacrylate)
2-Hydroxyethyl methacrylate (20 g, 0.154 moles), lauryl
methacrylate (30 g, 0.118 moles) and N,N-dimethylacetamide (DMA)(15
ml) were mixed together, polymerised to form a polymer, the polymer
was purified and dried, as described in Example 3. Yield=32.5
(65%)
Example 5
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg: Poly(polyethylene glycol mono
methacrylate-co-butyl acrylate-co-butyl methacrylate)
Methoxy (polyethyleneglycol) mono-methacrylate
(MW=550)(MPEG550)(5.0 g, 0.009 moles), butyl acrylate (20 g, 0.11 7
moles) and butyl methacrylate (25 g, 0.1 75 moles) were mixed
together. A 250 ml three-necked round bottom flask fitted with a
reflux condenser, thermometer and a nitrogen bleed was charged with
the above monomer solution in DMA and was heated to 80.degree. C.
with stirring. Polymerisation conditions, purifications steps and
drying procedure were performed as described in Example 3. Yield=40
g (80%)
Example 6
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg and a Chemically Bound Anti-coagulant (Heparin):
Heparin methacrylate-co-2-hydroxyethyl methacrylate-co-Butyl
acrylate-co-butyl methacrylate
Heparin methacrylate was synthesized according to procedures
detailed in commonly owned and assigned patent application
"Polysaccharide biomaterials and methods of use thereof",
PCT/GB02/02940. Heparin methacrylate (1 g) was dissolved in
2-hydroxyethyl methacrylate (15 g, 0.115 moles). Butyl acrylate (25
g, 0.195 moles), butyl methacrylate (10 g, 0.07 moles) and
dimethylsulphoxide (DMSO)(15 ml) were added to the heparin
methacrylate/2-hydroxyethyl methacrylate solution. A 250 ml
three-necked round bottom flask fitted with a reflux condenser,
thermometer and a nitrogen bleed was charged with the above monomer
solution in DMSO and was heated to 80.degree. C. with stirring.
Polymerization conditions, purifications steps and drying procedure
were performed as described in Example 3, above. Yield=35 g
(70%)
Example 7
Preparation of Copolymer with Monomeric Units of Predetermined
Difference in Tg: Preparation of Poly(glycerol mono
methacrylate-co-butyl acrylate-co-butyl methacrylate)
Glycerol mono-methacrylate (Rohm GmbH)(7.5 g, 0.047 moles), butyl
acrylate (10 g, 0.078 moles) and butyl methacrylate (32.5 g, 0.228
moles) were mixed together, polymerized to form a polymer, the
polymer was purified and dried, as described in Example 1. Yield=35
g (70%).
Example 8
Method of Coating Copolymers with Monomeric Units of Predetermined
Difference in Tg Associated with Therapeutic Agent Onto Medical
Device
Example 8 shows methods for applying polymers (e.g., copolymers) as
taught herein onto medical devices. A stainless steel coronary
stent is used for illustrative purposes. The copolymer,
poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate)(1.5 g) was
dissolved in tetrahydrofuran (THF)(100 ml). To a 20 ml aliquot of
the polymer solution was added the active agent paclitaxel (0.06
g). A stainless steel coronary stent (18 mm) was mounted onto a
rotating mandrel and air sprayed with the above solution of THF
containing polymer plus paclitaxel. The coated stent was vacuum
dried at 70.degree. C. for 30 minutes.
Paclitaxel loading on the stent was measured by incubating a coated
stent in acetonitrile (3 ml), vortexing (30 seconds) and then
measuring the absorbance at 227 nm wavelength; drug loading was
interpolated from a standard curve. Typical drug loading per stent
was 120 ug+/-10%.
Paclitaxel release profiles were performed in phosphate buffer
saline (PBS)(1.5 ml, pH7.4) at 37.degree. C. Readings were taken at
intervals of 1 hour, 24 hours or 48 hours. Quantification of
Paclitaxel was performed on HPLC, using a Nucleosil TM 100-5CIS
column (I.D.150 mm.times.4.6 mm) (Hichrome UK Ltd); mobile phase
50% water:50% acetonitrile; flow rate of 2.0 ml/min; column
temperature 55.degree. C.; detecting absorbance of 227 nm. FIG. 5
shows Paclitaxel release profiles at 37.degree. C. from 3 different
polymer compositions, as indicated. Persons of ordinary skill in
these arts, after reading this disclosure, will be able to apply
these methods to other medical devices. Polymers described or
taught herein may all be applied separately, in combination, and
with or without therapeutic agents using these methods.
Example 9
Preparation of Polymers (e.g., Copolymers) with Reactive Functional
Groups for Forming Covalent Bonds: poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate-methacrylate
Example 9 shows methods for decorating polymers (e.g., copolymers)
with a reactive functional group. In this case, the reactive
functional group is a reactive monomer, specifically, a
methacrylate. Polymers prepared by the methods of this Example may
be used, e.g., to form layers on a medical device or on other
layers.
The ter-polymer prepared in Example 2, poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate) (20.0 g) was
dissolved in tetrahydrofuran (THF)(100 ml, stabilizer free) in a
250 ml thick-walled glass bottle with cap. To this was added
isocyanatoethyl methacrylate (3.58 g) and dibutyltin dilaurate (0.2
g). The cap was screwed on tight and the solution was stirred for 3
hours at 60.degree. C. The THF was rotary evaporated off and the
product dried under vacuum at 40.degree. C. for 2 hours. Infrared
spectroscopy showed the disappearance of the stretching vibration
of N.dbd.C.dbd.O group at 2265 cm.sup.-1. A urethane bond was
formed between the hydroxyl group of the polymer and isocyanate
group of isocyanatoethyl methacrylate.
The presence of reactive methacrylate groups on the polymer was
demonstrated by dissolving 10 g of the ter-polymer in THF to which
was added a peroxide initiator bis(4-tertiary butyl cyclohexyl
peroxydicarbonate)(Perkadox 16)(0.5 g)(Akzo Nobel). A stainless
steel rod was coated with the polymer solution, air dried and then
placed in a vacuum oven at 80.degree. C. for 30 minutes. The coated
stainless steel rod was placed in the solvent 2-propanol for 5
minutes and examined using light microscopy. The polymer had
swelled with 2-propanol but did not detach from the stainless steel
rod. A similar sample was prepared but without heating in a vacuum,
and after incubating in 2-propanol, all of the polymer dissolved
away from the stainless steel rod. Persons of ordinary skill in
these arts, after reading this disclosure, will be able to, apply
these methods to other polymers, and will be able to incorporate
reactive functional groups as set forth herein.
Example 10
Formation of a Coating on a Medical Device having Two Layers of
Different Chemical Composition Covalently Crosslinked Together
This Example shows methods for applying polymers (e.g., copolymers)
as taught herein onto medical devices. A stainless steel coronary
stent is used for illustrative purposes. In this embodiment, a
first reactive polymeric layer is deposited, followed by a second
reactive polymeric layer containing a therapeutic agent, and an
initiator that works spontaneously was used.
The ter-polymer, poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate) (1.5 g)
prepared in Example 9 bearing methacrylate groups was dissolved in
THF (100 ml). Perkadox 16 (0.5 g) was then added to the above
solution. This polymer solution was air sprayed onto a stainless
steel coronary stent (1 8 mm) until a thin polymer film enveloped
the whole stent. The stent was air dried at 30.degree. C. for 1
hour.
To 20 ml of the above solution, Paclitaxel (0.06 g) was added and
sprayed onto the stent coated with polymer-methacrylate groups
until 120 ug+/-10% of Paclitaxel was loaded. The stent was placed
in a vacuum oven at 80.degree. C. for 30 minutes to cure the
coating. The methacrylates from the first layer react with the
methacrylates of the second layer, containing Paclitaxel, also, the
methacrylates in same layer react with each other to form the
crosslinked layer structure containing the therapeutic agent. The
stent was crimped onto a balloon catheter and expanded to a
diameter of 3 mm and light microscopy showed no cracks or
deformations. Consistent with results from Example 8, total
Paclitaxel loading on stent was 120 ug+/-10%.
Example 11
Alternative Embodiment of the Formation of a Coating on a Medical
Device having Two Layers of Different Chemical Composition
Covalently Crosslinked Together
A stainless steel coronary stent (18 mm) was coated as described in
Example 10 except after spraying the second polymer layer, the
coating was air dried at 30.degree. C. for 1 hour. The initiator
was initiated thermally. The coated stent was then sprayed with
heparin methacrylate (0.5% w/v in 2-propanol) containing Perkadox
16 (0.2% w/v) initiator. The coated stent was then placed in a
vacuum at 80.degree. C. for 30 minutes to cross-link the coating
and chemically link the heparin to the coating. The stent was then
placed in saturated sodium chloride solution for 30 seconds at
40.degree. C., to de-complex the heparin from benzalkonium
chloride, and washed with water. The stent was dyed with toluidine
blue and an intense purple colouration was indicative of heparin
being present. The purple colouration was homogenous throughout the
stent when examined by light microscopy. Stents were sprayed with
the above coatings, then sprayed with benzalkonium-heparin complex
(containing no methacrylate) and then placed in saturated sodium
chloride solution for 30 seconds at 40.degree. C., to de-complex
the heparin from benzalkonium chloride; when dyed with toluidine
blue, these showed no purple coloration. Heparin activity on stent
was measured using modified ant-factor Xa chromogenic assay.
Heparin activity was found to be 0.8 Units/ml equivalence.
Paclitaxel loading was 120 ug+/-10%.
FIG. 6 shows paclitaxel release in phosphate buffered physiological
saline at 37.degree. C. from stents containing polymer network and
polymer network with chemically bonded heparin. The results
demonstrate the incorporation of heparin onto the drug delivery
polymer has little effect on the delivery profile of
Paclitaxel.
Example 12
Incorporation of Heparin Azide onto Drug Delivery Polymer
Network
This Example demonstrates the use of photopolymerizaation to
covalently crosslink two layers together. Heparin azide was
synthesized according to the examples in patent application
"Polysaccharide biomaterials and methods of use thereof", U.S.
patent applications Ser. No. 10/179,453, filed Jun. 26, 2002, see
also U.S. patent applications Ser. No. 10/750,706, filed Jan. 5,
2004. A stainless steel coronary stent (18 mm) was coated as
described in Example 10, except after spraying the second polymer
layer, the coating was air dried at 30.degree. C. for 1 hour. The
above coated stent was then sprayed with heparin azide (0.5% w/v in
2-propanol) and then exposed to UV light from a medium pressure
mercury arc lamp for 2 minutes, to chemically link the heparin the
heparin to the coating via the azide group. The stent was the
placed in a vacuum oven at 80.degree. C. for 30 minutes, so that
the free reactive monomers were thereby polymerized using the
thermal initiator. The stent was then placed in saturated sodium
chloride solution for 30 seconds at 40.degree. C., to de-complex
the heparin from benzalkonium chloride, and then washed with water.
The stent was dyed with toluidine blue and an intense purple
coloration was indicative of heparin being present. The purple
coloration was homogenous throughout the stent when examined by
light microscopy. Heparin activity on the stent was measured using
modified ant-factor Xa chromogenic assay. Heparin activity was
found to be 0.7 Units/ml equivalence. Paclitaxel loading was 120
ug+/-10%. Paclitaxel release profile from the stent was very
similar to the profile from Example 11.
Example 13
Coating of a Medical Device with a First Layer having a Reactive
Functional Group that is Crosslinked to Functional Groups on a
Second Layer that is Polymerized on the First Layer
This Example shows the formation of a plurality of layers on a
medical device and methods of crosslinking the layers. The
therapeutic agents is associated with the outermost layer. The
copolymer as prepared in Example 9, poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate) (1.5 g) was
dissolved in tetrahydrofuran (THF)(100 ml), and Perkadox 16 (0.5 g)
was dissolved in the above solution. This solution was air sprayed
onto a stainless steel coronary stent (18) until a thin polymer
film was enveloped the whole stent. The stent was air dried at
30.degree. C. for 1 hour.
To THF (20 ml) was added Paclitaxel (0.06 g), Methoxy (polyethylene
glycol) mono-methacrylate (MW=2000)(0.25 g), lauryl methacrylate
(0.5 g), butyl methacrylate (4.0 g), ethylene glycol dimethacrylate
(0.02 g) and Perkadox 16 (0.10 g). The stent was air sprayed with
the above monomer solution until a Paclitaxel loading of 120
ug+/-10% was achieved. The coating was cured in an oven at
80.degree. C. with an atmosphere of nitrogen for 1 hour. FIG. 7
shows Paclitaxel release from the stent in phosphate buffered
physiological saline at 37.degree. C., where the reactive monomers
have been linked together to form a cross-linked polymer
network.
Example 14
Alternative Embodiment of a Coating of a Medical Device with a
First Layer having a Reactive Functional Group
that is Crosslinked to Functional Groups on a Second Layer that is
Polymerized on the First Layer
In this Example, the monomers containing the active agent
(Paclitaxel) were cross-linked and cured into a polymeric network
by the use of UV light. As in Example 13, all the conditions were
the same except a UV initiator was used, benzoin methyl ether,
rather than Perkadox. After spraying the stent with monomers
containing Paclitaxel and benzoin methyl ether on the rotating
mandrel, the stent was exposed to UV light from a medium pressure
mercury arc lamp in an atmosphere of nitrogen for a period of 10
minutes. The stent was examined using light microscopy. The
monomers had cured to form a cross-linked network film containing
the active agent, Paclitaxel.
Example 15
Loading of Layer(s) with a Therapeutic Agent
This Example shows a method for loading a therapeutic agent into a
coating or certain layer(s). In this methods, the layers were
deposited without the therapeutic agent, and were loaded after the
layers were secured to the device. Introduction of a therapeutic
agent (Paclitaxel) into the layers was performed by swelling the
cross-linked layers with a solvent plus the agent, Paclitaxel. The
ter-polymer as prepared in Example 9, poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate)(1.5 g) was
dissolved in tetrahydrofuran (THF)(100 ml), Perkadox 16 (0.5 g) was
dissolved in the above solution. The polymer solution was air
sprayed onto a stainless steel coronary stent (18) until a thin
polymer film was enveloped the whole stent. The stent was air dried
at 80.degree. C. for 1 hour. The stent was placed in 20 ml 80/20
solution of 2-propanol/THF containing Paclitaxel (0.2 g) for 2
minutes. The stent was removed and air dried at 60.degree. C. for
30 minutes. Paclitaxel loading was found to be 80 ug+/-10%.
Therefore the cross-linked coating swelled in the above solution,
allowing absorption of Paclitaxel into the polymer network and
trapping it when air dried at 60.degree. C.
Example 16
Alternative Embodiment of Loading of Layer(s) with a Therapeutic
Agent
This Example shows another method of introducing an agent into a
coating or layer(s) after they are formed. The methods described in
Example 13 were followed, except the composition of reactive
monomers did not contain Paclitaxel. The coating was cured at
80.degree. C. in an oven in an atmosphere of nitrogen for 1 hour.
The stent was placed in 20 ml 80/20 solution of 2-propanol/THF
containing Paclitaxel (0.2 g) for 2 minutes. The stent was removed
and air dried at 60.degree. C. for 30 minutes. Paclitaxel loading
was found to be 130 ug+/-10%.
Example 17
Method for Coating a Medical Device with a Coating having a
Therapeutic Agent and a First Layer with a Reactive Functional
Group Crosslinked to a Second Layer
This Example shows a method for layering a device with a first
layer that is crosslinkable to a second layer. In this case, the
second layer is a copolymer having a therapeutic agent. Poly(vinyl
chloride-co-vinyl acetate-co-vinyl alcohol)(20 g) was dissolved in
anhydrous THF (100 ml stabiliser free) in a 250 ml thick walled
glass bottle with cap. To this was added isocyanatoethyl
methacrylate (4.23 g) and dibutyltin dilaurate (0.2 g). The cap was
screwed on tight and the solution was stirred for 3 hours at
60.degree. C. As in Example 9, the polymer was processed and
characterised by infrared, and functionally tested for methacrylate
activity, showing that the isocyanate had linked to the vinyl
alcohol of the above polymer forming a urethane linkage. This
polymer was then dissolved in THF to give a 2% w/v solution
containing Perkadox (0.2% w/v) and sprayed onto one side of a
stainless steel disc, with a diameter of 11 mm, having a similar
surface area to a 18 mm coronary stent. The coated disc was then
air-dried at 30.degree. C. for 1 hour. Poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate) (1.5 g) bearing
methacrylate groups, see Example 9, was dissolved in
tetrahydrofuran (THF)(100 ml), containing Perkadox 16 (0.5 g). To a
20 ml aliquot of this solution Paclitaxel (0.6 g) was added and air
sprayed onto the disc until a loading of 120 ug+/-10% was achieved.
The coating was cured at 80.degree. C. in a vacuum oven. The
Paclitaxel release profile was determined as previously described
(not shown) and was similar to that obtained in FIG. 6.
Example 18
Alternative Method for Coating a Medical Device with a Coating
having a Therapeutic Agent and a First Layer with a Reactive
Functional Group Crosslinked to a Second Layer
This Example shows another method for layering a device with a
first layer that is crosslinkable to a second layer. A reactive
copolymer having reactive functional groups is prepared and used
for the first layer. In this Example, the reactive copolymer bears
isocyanate groups.
Preparation of poly(isocyanatoethyl methacrylate-co-butyl
acrylate-co-butyl methacrylate
In this embodiment, the method involves preparation of
poly(isocyanatoethyl methacrylate-co-butyl acrylate-co-butyl
methacrylate). Isocyantoethyl methacrylate (20 g, 0.129 moles),
butyl acrylate (20 g, 0.156 moles) and butyl methacrylate (10 g,
0.07 moles) were mixed together. A 250 ml three-necked round bottom
flask fitted with a reflux condenser, thermometer and a nitrogen
bleed was charged with the above monomer solution and was heated to
80.degree. C. with stirring. Polymerization was initiated with the
addition of 2,2'-azobis-(2-methylbutyronitrile) (0.8 g). The
reaction was allowed to proceed for 30 minutes, and then benzoyl
peroxide (1.15 g)(40% wt. Blend in dibutyl phthalate) was added.
The reaction proceeded for a further 60 minutes. The temperature of
the reaction was kept at 100.degree. C.+/-5.degree. C. Upon cooling
the above viscous mixture, THF (stabilizer free)(50 ml) was added
and then poured into petroleum ether (100-120.degree. C.)(500 ml)
to precipitate the polymer. The precipitated polymer was washed
twice with 300 ml of petroleum ether and then dried in a vacuum
oven at 60.degree. C. for 2 hours. Yield=40 g (80%). Infrared
spectroscopy showed a sharp stretching vibration of N.dbd.C.dbd.O
group at 2265 cm.sup.-1.
Coating
A 1.5% w/v solution in THF of the above polymer was prepared and
air sprayed onto one side of a stainless steel disc, with a
diameter of 11 mm, having a similar surface area to a 18 mm
coronary stent. The coated disc was then air-dried at 40.degree. C.
for 30 minutes. Polyvinylpyrrolidone (PVP)(average MW=1,300,000)(1
g) was dissolved in 2-propanol (100 ml) and sprayed onto the disc
until an even coat was achieved and dried in an oven at 80.degree.
C. for 5 hours. The disc was immersed in water and become highly
wettable, in addition the surface was lubricious. The lubricity did
not diminish even after repeated and vigorous rubbing between thumb
and forefinger. These results indicate that the outermost layer was
covalently linked to the innermost layer.
Another disc was also treated in a similar fashion but this time
Paclitaxel was added to the PVP, (0.04 g Paclitaxel in 20 ml of 1%
w/v PVP in 2-propanol), and dried in an oven at 80.degree. C. for 5
hours. Paclitaxel loading was determined to be 120 ug+/-10% and
FIG. 8 shows a fast release profile when tested in phosphate
buffered physiological saline at 37.degree. C.
Example 19
Preparation of Polymer Bearing Amine Groups as First Layer to
Chemically Link a Second Polymeric Layer Containing Active Agent
and thus Forming a Polymeric Network
Preparation of poly(aminoethyl methacrylate hydrochloride-co-butyl
acrylate-co-butyl methacrylate)
2-Aminoethyl methacrylate hydrochloride (10 g, 0.06 moles), butyl
acrylate (20 g, 0.156 moles), butyl methacrylate (20 g, 0.14 moles)
and N,N-dimethylacetamide (DMA)(20 ml) were mixed together. A 250
ml three-necked round bottom flask fitted with a reflux condenser,
thermometer and a nitrogen bleed was charged with the above monomer
solution and was heated to 80.degree. C. with stirring.
Polymerization was initiated with the addition of
2,2'-azobis-(2-methylbutyronitrile) (0.8 g). The reaction was
allowed to proceed for 30 minutes, and then benzoyl peroxide (1.15
g)(40% wt. blend in dibutyl phthalate) was added. The reaction
proceeded for a further 60 minutes. The temperature of the reaction
was kept at 100.degree. C.+/-5.degree. C. After cooling the above
viscous polymer, was poured into 2-propanol (50 ml) and then added
to water (1000 ml) to precipitate the polymer. The polymer was
washed a further 3 times (3.times.1000 ml water) and then frozen
and freeze dried. The polymer was processed (further purification)
as described in Example 3. Yield=33 g (66%)
Coating
1.5 g of the above polymer was dissolved in 2-proppanol and sprayed
onto a stainless steel coronary stent (18 mm) and then dried at
80.degree. C. for 1 hour. The coated stent was immersed in 0.1% w/v
sodium hydroxide in water/methanol (75:25) solution to form the
free base of aminoethyl methacrylate portion of the polymer. The
stent was washed in water and dried at 60.degree. C. for 30
minutes. The stent was air sprayed with 0.2% isocyanatoethyl
methacrylate in methanol and dried in an oven at 50.degree. C. for
10 minutes. The stent was washed with aqueous methanol (50:50) to
remove unreacted isocyanatoethyl methacrylate and dried at
50.degree. C. for 5 minutes. The second layer of the polymer
containing the active agent was sprayed onto the stent as described
in Example 10.
Example 20
Coating with a Plurality of Layers, with a Second Layer Applied to
a First Layer to Slow Release of a Therapeutic Agent from the First
Layer
This Example shows the formation of a plurality of layers on a
device. In this embodiment, one of the layers has a therapeutic
agent and the other layer does not. The layer without the agent is
applied to slow release of the agent in the layer where the agent
is initially disposed. The second polymer layer helps to control
the diffusion of the active agent into the bulk. From Example 8,
polymer plus Paclitaxel was coated onto the stent. A second layer
of polymer poly(hydroxyethyl
methacrylate-co-butylacrylate-co-butylmethacrylate)(1.5% w/v) was
dissolved in tetrahydrofuran (THF) and sprayed onto the first
polymer layer containing Paclitaxel and dried at 80.degree. C. for
30 minutes.
Example 21
Alternative Embodiment of a Coating with a Plurality of Layers,
with a Second Layer Applied to a First Layer to Slow Release of a
Therapeutic Agent from the First Layer
In this Example, the therapeutic agent is in the first polymer
layer. And, the first layer and the second layer bear reactive
functional groups that are able to react to crosslink link the two
polymer layers. The second cross-linked layer helps to further
control the release of the therapeutic agent, in this instance,
Paclitaxel. All conditions are identical to Example 20 except that
the polymer used for both the first and second layer is from
Example 9, and Perkadox 16 (initiator) had been added and the
coating cured at 80.degree. C. in a vacuum for 30 minutes. FIG. 9
shows the release profile of Paclitaxel from these two systems in
phosphate buffered physiological saline at 37.degree. C.
The embodiments above are intended to be illustrative and not
limiting. All patents, patent applications, and publications
referenced herein are hereby incorporated by reference herein.
* * * * *